Patent Publication Number: US-2022235419-A1

Title: Risk Evaluation of Genomic Susceptibility to Opioid Addiction

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application 62/856,812, filed Jun. 4, 2019. The entire contents of the aforementioned application are hereby incorporated by reference in its entirety, including drawings. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates to methods of treating, assessing or preventing opioid use disorder (OUD), and more specifically, obtaining and utilizing a risk score for assessing a genetic predisposition to opioid addiction or opioid addiction relapse in a subject using a plurality of pre-determined alleles. 
     BACKGROUND 
     There is a growing opioid problem in the United States. This national epidemic has been recognized by the Federal government, with pledged support and requests to develop precision medicine based solutions. Prescription drug abuse has led to health problems, addiction, and death. In the United States, 44 people die every day from an overdose of prescription painkillers, more than cocaine and heroin combined. 
     In the United States, opioid overdose deaths increased by 265% among men and 400% among women between 1999 and 2010. There has been a consistent increase in the prevalence of opioid use disorder (OUD), resulting in medical complications (i.e., nonfatal overdoses), falls and fractures, drug-drug interactions and neonatal conditions. These complications result in costly, preventable expenditures and a great amount of emotional suffering. The opioid epidemic impacts people of all ages, from infants and children to the elderly. 
     Accordingly, there is a need for techniques able to address and assess risk of opioid addiction and opioid deaths in the United States and across the world. 
     SUMMARY 
     In some aspects, the present disclosure provides a method of assessing whether a subject is at risk of opioid addiction, the method comprising: 
     (1) determining the presence of a plurality of pre-determined alleles in a biological sample from the subject by assigning a plurality of counts, wherein the plurality of pre-determined alleles comprise two or more genomic targets selected from Table 1; 
     (2) determining a risk score based upon summing the plurality of counts; and 
     (3) comparing the risk score with one or more predetermined reference values, wherein the subject is determined to have a risk level of opioid addiction if the risk score is greater than a threshold value using a SNP model. 
     In other embodiments, the methods comprise obtaining and utilizing an opioid use disorder (OUD) risk score for assessing a genetic predisposition to opioid addiction, the method comprising: 
     (1) obtaining a biological sample from a subject; 
     (2) performing an allelic analysis on the biological sample to determine the presence of a plurality of pre-determined alleles, wherein the plurality of pre-determined alleles comprise two or more genomic targets selected from Table 1; 
     (3) assigning a count for each of the alleles in the plurality of pre-determined alleles that was present in the biological sample; 
     (4) determining a risk score based upon a total count using a SNP Model, wherein the risk score identifies a severity of the genetic predisposition to opioid addiction; and 
     (5) administering a medical assisted treatment procedure based on the risk score identified in the subject. 
     In further embodiments, the methods comprise obtaining and utilizing a relapse risk score for assessing a genetic predisposition to addiction relapse, the method comprising: 
     (1) obtaining a biological sample from a subject; 
     (2) performing an allelic analysis on the biological sample to determine the presence of a plurality of pre-determined alleles, wherein the plurality of pre-determined alleles comprise two or more genomic targets selected from Table 1; 
     (3) assigning a count for each of the alleles in the plurality of pre-determined alleles that was present in the biological sample; 
     (4) determining a risk score based upon a total count using a SNP Model, wherein the risk score identifies a severity of the genetic predisposition to addiction relapse; and 
     (5) administering a medical assisted treatment procedure based on the risk score identified in the subject. 
     In other embodiments, the methods include assessing whether a subject is at risk of opioid addiction, the method comprising: 
     (1) determining the presence of a plurality of pre-determined alleles in a biological sample from the subject by assigning a plurality of counts, wherein the plurality of pre-determined alleles comprises two or more genomic targets selected in Table 1; 
     (2) determining a risk score based upon summing the plurality of counts; 
     (3) comparing the risk score with a predetermined reference value using a SNP Model, wherein the subject is determined to be at high risk of opioid addiction if the risk score is greater than a threshold value as compared to those subjects where the risk score is lower than the threshold value; and 
     (4) administering a medical assisted treatment procedure based on the risk score identified in the subject. 
     In still other embodiments, the methods include obtaining and utilizing a relapse risk score for assessing a genetic predisposition to addiction relapse, the method comprising: 
     (1) obtaining a biological sample from a subject; 
     (2) performing an allelic analysis on the biological sample to determine the presence of a plurality of pre-determined alleles by assigning a plurality of counts, wherein the plurality of pre-determined alleles comprise one or more genomic targets selected from Table 1; 
     (3) determining a risk score based upon summing the plurality of counts; and 
     (4) comparing the risk score with one or more predetermined reference values, wherein the subject is determined to have a risk level of opioid addiction if the risk score is greater than a threshold value using a SNP model. 
     In some embodiments, the SNP model comprises a sex-stratified single count SNP model, a sex-stratified double count SNP model, a non-sex-stratified single count SNP model, or any combinations thereof. 
     In some embodiments, the medical assisted treatment procedure comprises monitoring the subject, prescribing an increase dose, prescribing a decreased dose, transitioning the subject from inpatient to outpatient rehabilitation, transitioning the subject from outpatient to inpatient rehabilitation, or any combinations thereof. 
     In some embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele C+ of gene BDNFOS/antiBDNF (rs11030096); 
     allele A+ of gene DRD2 (rs1079596); 
     allele G+ of gene DRD2 (rs1125394); 
     allele C+ of gene DRD3 (rs9288993); 
     allele T/T of gene GABRB3 (rs4906902); 
     allele C/C of gene OPRM1 (rs510769); 
     allele T/T of gene TACR1 (rs735668); 
     allele T/T of gene ZNF804A (rs7597593); 
     allele C+ of gene DRD3 (rs2654754); and/or allele A/A of gene OPRM1 (rs1799971). 
     In other embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele A/A of gene CNR1 (rs2023239); 
     allele G+ of gene TACR3 (rs4530637); 
     allele C+ of gene TACR3 (rs1384401); 
     allele T/T of gene EXOC4 (rs718656); 
     allele T+ of gene DRD3 (rs324029); 
     allele G+ of gene DRD3 (rs6280); 
     allele G/G of gene CNR1 (rs6928499); 
     allele G/G of gene CYPB6 (rs3745274); and/or 
     allele C/C of gene CYP2D6 (rs1065852). 
     In further embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele C/C of gene CNIH3 (rs1369846); 
     allele A/A of gene CNIH3 (rs1436171); 
     allele A/A of gene GRIN3A (rs17189632); 
     allele C+ of gene HTR3B (rs11606194); 
     allele C/C of gene OPRD1 (rs2234918); 
     allele G/G of gene WLS (rs1036066); 
     allele G+ of gene intergenic (rs965972); 
     allele C/C of gene MTHFR (rs1801133); and/or 
     allele G/G of gene MTHFR (rs1801133). 
     In some embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele T/T of gene DRD3 (rs9825563); 
     allele T/T of gene GAL (rs948854); 
     allele C+ of gene NR4A2 (rs1405735); 
     allele A+ of gene OPRM (rs9479757); and/or 
     allele T+(A+) of gene CYP3A4 (rs35599367). 
     In some embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     chr11:113399438 of gene ANKK1; 
     chr11:27643996 of gene BDNFOS/antiBDNF; 
     chr1:224706393 of gene CNIH3; 
     chr6:88150763 of gene CNR1; 
     chr16:3745362 of gene CREBBP; 
     chr22:38287631 of gene CSNK1E; 
     chr11:113425897 of gene DRD2; 
     chr11:113441417 of gene DRD2; 
     chr11:113426463 of gene DRD2; 
     chr11:113414814 of gene DRD2; 
     chr11:113412966 of gene DRD2; 
     chr11:113425564 of gene DRD2; 
     chr3:114162776 of gene DRD3; 
     chr3:114140326 of gene DRD3; 
     chr11:636784 of gene DRD4; 
     chr15:26774621 of gene GABRB3; 
     chr19:1005231 of gene GABRB3; 
     chr1:163535374 of gene intergenic g.163535374G; 
     chr1:28855013 of gene OPRD1; 
     chr1:28863085 of gene OPRD1; 
     chr6:154040884 of gene OPRM1; 
     chr8:56447926 of gene PENK; 
     chr5:1446274 of gene SLC6A3; 
     chr2:75198602 of gene TACR1; 
     chr2:75135918 of gene TACR1; 
     chr4:103643921 of gene TACR3; 
     chr4:103585232 of gene TACR3; 
     chr1:68194522 of gene WLS; 
     chr2:184668853 of gene ZNF804A; and/or 
     chr2:184913701 of gene ZNF804A. 
     In some embodiments, the plurality of pre-determined alleles further comprise at least one allele selected from the group consisting of: 
     chr6:154039662 of gene OPRM1 118A&gt;G; 
     chr19:41006936 of gene CYP2B6*13*6*7*9+516G&gt;T; 
     chr22:42130692 of gene CYP2D6*4*10*1 4A+100C&gt;T; 
     chr1:11796321 of gene MTHFR 677C&gt;T; 
     CYP2C9 non EM (IM or PM); and/or 
     chr7:99768693 of gene CYP3A4*22 intron6 15389C&gt;T. 
     In some embodiments, the opioid addiction risk is opioid use disorder (OUD) or relapse risk. 
     In further embodiments, the subject is a female or male. 
    
    
     
       BRIEF DESCRIPTION OF FIGURES 
       The following figures are provided by way of example and are not intended to limit the scope of the invention. 
         FIG. 1  plots an opioid use disorder receiver operating characteristic curve for a female using a sex-stratified single count SNP Model 1. 
         FIG. 2  plots an opioid use disorder receiver operating characteristic curve for a male using a sex-stratified single count SNP Model 1. 
         FIG. 3  plots a relapse receiver operating characteristic curve for a female using a sex-stratified single count SNP Model 1. 
         FIG. 4  plots a relapse receiver operating characteristic curve for a male using a sex-stratified single count SNP Model 1. 
     
    
    
     DETAILED DESCRIPTION 
     Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Accordingly, the following terms are intended to have the following meanings: 
     As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. 
     As used herein, “administration” of a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e.g., as described herein. 
     As used herein, the term “and/or,” when used in a list of two or more items, means that any one of the listed items can be employed by itself, or any combination of two or more of the listed items can be employed. For example, if a composition is described as comprising components A, B, and/or C, the composition can contain A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C in combination. 
     As used herein, “treatment” and “treating”, are used interchangeably herein, and refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. The term “treat”, in all its verb forms, is used herein to mean to relieve, alleviate, prevent, and/or manage at least one symptom of a disorder in a subject. 
     As used herein, “subject” or “patient” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject. 
     As used herein, “opioid use disorder” is a problematic pattern of opioid use that causes significant impairment or distress. A diagnosis is based on specific criteria such as unsuccessful efforts to cut down or control use, or use resulting in social problems and a failure to fulfill obligations at work, school, or home, among other criteria. Opioid use disorder has also been referred to as “opioid abuse or dependence” or “opioid addiction.” 
     As used herein, “relapse risk” is the risk of recurrence of opioid use disorder that has gone into remission or recovery. During the recovery process, subjects may become exposed to certain triggers or have genomic predisposition that increase the risk of returning to opioid use disorder or addiction. 
     Deoxyribonucleic acid “DNA” is a molecule composed of two chains that coil around each other to form a double helix carrying the genetic instructions used in the growth, development, functioning, and reproduction of all known organisms. DNA and ribonucleic acid (RNA) are nucleic acids; alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for a subject&#39;s functioning and development. 
     The two DNA strands are also known as polynucleotides as they are composed of simpler monomeric units called nucleotides. Each nucleotide is composed of one of four nitrogen-containing nucleobases (cytosine [C], guanine [G], adenine [A] or thymine [T]), a sugar called deoxyribose, and a phosphate group. The nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules (A with T and C with G), with hydrogen bonds to make double-stranded DNA. 
     A single-nucleotide polymorphism “SNP” is a substitution of a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population. For example, at a specific base position in the human genome, the C nucleotide may appear in most individuals, but in a minority of individuals, the position is occupied by an A. This means that there is a SNP at this specific position, and the two possible nucleotide variations—C or A—are said to be alleles for this position. For purposes of this disclosure, in certain embodiments, “allele” refers to genetic material, including, but not limited to, one or more DNA fragments, present in biological samples, in vitro, corresponding to one or both alleles of a SNP at a specific position. SNPs denote differences in a subject&#39;s susceptibility or risk to a wide range of diseases including opioid use disorders and relapse risk. The severity of risks and the way the body responds to treatments are also manifestations of genetic variations. 
     Pharmacogenomic Testing for Opioid Addiction 
     Genetics plays an important role in how an individual metabolizes and responds to medications, including opioids prescribed for pain management and those used for medication assisted treatment (MAT) of opioid use disorder (OUD). With a high rate of opioid and OUD medication use, solutions for improving prescribing, treatment, and prevention are in great need. 
     Precision Medicine is an approach to patient care that describes a paradigm in which treatment and prevention plans are tailored to incorporate the individual&#39;s genetic variability. Pharmacogenomics (PGX) is at the forefront of precision medicine. PGX applies the knowledge of an individual&#39;s genetics to drug response and helps determine if the patient will have an adverse or therapeutic response to a particular medication. It is estimated that 20 to 95% of the variability in a patient&#39;s response to drugs is associated with genetics. If a patient has a genetic variant, the drug may be metabolized too slowly (causing toxic levels to build up) or too quickly (resulting in a lack of therapeutic efficacy). PGX testing provides the genetic information necessary to direct more accurate prescribing for each patient. 
     Pharmacogenomic testing provides valuable information regarding an individual&#39;s ability to respond to specific drugs. Despite the potential to improve healthcare quality and reduce costs, implementation into routine clinical practice has been slow. This is in large part, due to the lack of studies that assess clinical utility. Early evidence suggests that genetic variability plays a role in the response to addiction treatment medications. For example: 1) genetic mutations in OPRM1 are associated with the efficacy of naltrexone (VIVITROL®), 2) genetic variability in the CYP2B6 enzyme is associated with methadone plasma concentrations and clearance, and 3) buprenorphine (SUBOXONE®) efficacy is associated with mutations in OPRD1. In addition, the efficacy of buprenorphine (SUBOXONE®) may be further reduced if the patient is taking other medications that work through the same metabolic pathways or have a genetic aberration in specific metabolizing enzymes. PGX analysis may help identify the most effective anti-addictive medication for each patient and improve the long-term success of recovery. 
     As disclosed herein, the examples demonstrates the relationship between mutations in specific drug metabolizing genes and addiction recovery. Given the limited treatment options and low treatment success rates, improved methods for treating a growing population health problem such as OUD are in great need. 
     In addition to the genes that regulate opioid metabolism and drug efficacy, other genes related to addiction risk have been identified. It is believed that up to 50% of addiction is related to genetics. Understanding a patient&#39;s genetic predisposition or susceptibility to addiction may be useful for: 1) helping addicts understand their disease has a genetic component; 2) shifting blame and stigma to a genetic predisposition may help to improve addiction treatment success; and 3) identifying patients at risk of developing an addiction and preventing the growth of OUD and relapse. 
     The disclosure herein demonstrates PGX testing can improve initial opioid prescribing practices for MAT of OUD and the relationship between mutations in specific drug metabolizing genes and addiction recovery. This approach includes analysis of addiction risk genes in all patients recruited to validate their association in a clinical population. These genes may be useful for identifying patients at risk for addiction at the initial point of prescribing and for identifying OUD patients who may face greater recovery challenges because of their susceptibility to relapse. The addiction risk panel provided in Table 1 contains 180 addiction risk mutations, including single nucleotide polymorphisms (SNPs). SNPs are the most common type of genetic variation among people and represent a difference in a single DNA nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a given stretch of DNA. 
     The scoring SNP Models and algorithms disclosed herein could be used as tools when a health care team is making a treatment plan for a patient who will be prescribed opioids (addiction risk) or will be treating an addiction (relapse risk). Possible benefits to knowing the following levels of risk may include: 
     High risk of OUD: Evaluate the risk and benefits to prescribing opioids, increase caution about the quantities of opioids prescribed and dispensed; increase monitoring by a health care professional between visits, assess for addiction more frequently; include a conservative time frame for opioid use; intentionally tapering off the opioid and providing resources for patients with high risk of OUD; consider the use of non-opioid therapies (i.e. adjuvant therapies), alone or in combination, depending on the type &amp; source of pain. 
     Low risk of OUD: As low risk does not mean no risk, caution should be given to interpreting low risk as this does not mean that opioids can be freely used or that caution should be reduced from current levels. Evaluate the risk and benefits to prescribing opioids; establish a monitoring plan, which may be less frequent than someone at high risk of OUD; minimize monitoring of addiction over time to save on health care resources; increase caution about the amount of opioids prescribed initially and between visits. While someone may have a low risk of OUD, it is known that prescribing opioids can lead to increased tolerance, dependence and addiction; therefore, the use of non-opioid therapies (i.e. adjuvant therapies), alone or in combination, depending on the type &amp; source of pain, can be considered. 
     High risk of relapse: Potentially justify a longer inpatient rehabilitation stay, a longer duration of intensive outpatient rehabilitation; potentially help guide a patient to know that extra work must be done. 
     Low risk of relapse: As low risk does not mean no risk, caution should be given to interpreting low risk (MAT may still require monitoring/support), or that caution should be reduced from current levels. Potentially justify an earlier transition from inpatient rehabilitation to intensive outpatient rehabilitation. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Full Opioid Panel having 180 SNPs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Assay Names used 
                 NCBI SNP 
                 Gene 
                   
                   
               
               
                   
                 in Addiction Panel 
                 Reference 
                 Symbol 
                 CHR 
                 Context Sequence [VIC/FAM] 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 ABCB1/ MDR1, 
                 rs1045642 
                 ABCB1/ 
                 7 
                 TGTTGGCCTCCTTTGCTGCCCTCAC[   A/G   ]A 
               
               
                   
                 c.3435T &gt; C 
                   
                 MDR1 
                   
                 TCTCTTCCTGTGACACCACCCGGC 
               
               
                   
               
               
                 2 
                 ANKK1, c.1469A &gt; G 
                 rs2734849 
                 ANKK1 
                 11 
                 TCCCGTCAGGCTGACCCCAACCTGC[   A/G   ]T 
               
               
                   
                   
                   
                   
                   
                 GAGGCTGAGGGCAAGACCCCCCTC 
               
               
                   
               
               
                 3 
                 ANKK1/DRD2, 
                 rs1800497 
                 ANKK1/ 
                 11 
                 CACAGCCATCCTCAAAGTGCTGGTC[   A/G   ] 
               
               
                   
                 17316G &gt; A Taq1A 
                   
                 DRD2 
                   
                 AGGCAGGCGCCCAGCTGGACGTCCA 
               
               
                   
               
               
                 4 
                 ARHGAP28, 
                 rs2567261 
                 ARHGAP 
                 18 
                 GAACCACTGGCAGGTACACTTTAAA[   C/T   ] 
               
               
                   
                 c.334 + 692T &gt; C 
                   
                 28 
                   
                 GGGTGAATCGAATGGCATGTGAAGT 
               
               
                   
               
               
                 5 
                 AUTS2, c.661- 
                 rs6943555 
                 AUTS2 
                 7 
                 AGCCCTCATTCTAATAGTAAGGCTG[   A/T   ]T 
               
               
                   
                 94715T &gt; A 
                   
                   
                   
                 TTCCTCTTTTCCAATGTTTATGTA 
               
               
                   
               
               
                 6 
                 BDNF, c.196G &gt; A 
                 rs6265 
                 BDNF 
                 11 
                 TCCTCATCCAACAGCTCTTCTATCA[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 TGTTCGAAAGTGTCAGCCAATGAT 
               
               
                   
               
               
                 7 
                 BDNF, c.−21- 
                 rs11030104 
                 BDNF 
                 11 
                 ATTAAAAAGCAGATAACACTACCAC[   A/G   ] 
               
               
                   
                 4385T &gt; C 
                   
                   
                   
                 TACTAACTGTCCTACAATTTCCTGT 
               
               
                   
               
               
                 8 
                 BDNF, c.− 
                 rs10767664 
                 BDNF 
                 11 
                 GTAGGCTTGACATTGACATGTTTTT[   A/T   ]C 
               
               
                   
                 22 + 16205A &gt; T 
                   
                   
                   
                 TATTAATAATTTTAATTGGCTGAG 
               
               
                   
               
               
                 9 
                 BDNF, c.25- 
                 rs16917234 
                 BDNF 
                 11 
                 CTCTTGAACTCAGTCCTGAAAATAA[   C/T   ]G 
               
               
                   
                 18242A &gt; G 
                   
                   
                   
                 TTAATAGCTGAGAAAAGAGCATTG 
               
               
                   
               
               
                 10 
                 BDNFOS/antiBDNF, 
                 rs988712 
                 BDNFOS/ 
                 11 
                 ATTCTGGAATTTATATGAAAAGACC[   G/T   ]T 
               
               
                   
                 n.144 + 1719G &gt; T 
                   
                 antiBDNF 
                   
                 ATAGCATAGGGACAATAGTTAAAA 
               
               
                   
               
               
                 11 
                 BDNFOS/antiBDNF, 
                 rs7481311 
                 BDNFOS/ 
                 11 
                 TCCATTGGTCATGTCAGCACTGCTA[   T/C   ]T 
               
               
                   
                 n.144 + 21466T &gt; C 
                   
                 antiBDNF 
                   
                 GTTGGGCTCAAAGGCTGAGATAGT 
               
               
                   
               
               
                 12 
                 BDNFOS/antiBDNF, 
                 rs11030096 
                 BDNFOS/ 
                 11 
                 TACACAGGTGAATGAAAATGTCCAC[   C/T   ] 
               
               
                   
                 n.305 + 3991T &gt; C 
                   
                 antiBDNF 
                   
                 GCTCTAGAAGAGTTTATACAAATAA 
               
               
                   
               
               
                 13 
                 CACNA2D2, 
                 rs5030977 
                 CACNA2 
                 3 
                 TGTACTGGGCCCAGGTCAGGGTAGC[   C/T   ] 
               
               
                   
                 c.1260 + 22G &gt; A 
                   
                 D2 
                   
                 CCTGCCTCGGTTGAGCCTCACCGTC 
               
               
                   
               
               
                 14 
                 CNIH3, 
                 rs1369846 
                 CNIH3 
                 1 
                 CAGGCAATGACGCACATAGCATCCT[   C/T   ] 
               
               
                   
                 c.198 + 21550C &gt; T 
                   
                   
                   
                 GCCTGTTCCGGAGGGTCGCCTTTGA 
               
               
                   
               
               
                 15 
                 CNIH3, 
                 rs1436171 
                 CNIH3 
                 1 
                 AGAGCTTCCACCCAGAGAAGTTGAC[   A/G   ] 
               
               
                   
                 c.198 + 9283A &gt; G 
                   
                   
                   
                 GCAGACAGATGTTGCCAGCTGCCAG 
               
               
                   
               
               
                 16 
                 CNIH3, c.199- 
                 rs1436175 
                 CNIH3 
                 1 
                 TCATCTGCCCCGTGCTGAGTAACTA[   A/G   ]A 
               
               
                   
                 9798G &gt; A 
                   
                   
                   
                 GGCAGAAGATGACCTGTTTCTGCC 
               
               
                   
               
               
                 17 
                 CNIH3, 
                 rs10799590 
                 CNIH3 
                 1 
                 CCCCCTGCCCAGTTACCCTGCATCT[   A/G   ]T 
               
               
                   
                 c.81 + 17525G &gt; A 
                   
                   
                   
                 TCTGTGTTGAGCAGAGGTGTTCAA 
               
               
                   
               
               
                 18 
                 CNIH3, 
                 rs12130499 
                 CNIH3 
                 1 
                 GTCTGCAGTCAGATTAGTAACTATT[   C/T   ]C 
               
               
                   
                 c.81 + 31557C &gt; T 
                   
                   
                   
                 TTCCTGGTAGGACAAGAGCAAAAG 
               
               
                   
               
               
                 19 
                 CNIH3, c.82- 
                 rs298733 
                 CNIH3 
                 1 
                 AAACTAGGTGTGACCTCAGTAGACA[   A/C   ] 
               
               
                   
                 26409C &gt; A 
                   
                   
                   
                 TGATTTTAGCCACTGTTGATGCCTG 
               
               
                   
               
               
                 20 
                 CNR1, c.−63- 
                 rs2023239 
                 CNR1 
                 6 
                 TAGGTTTGTGGATGTGCCAGGACCA[   C/T   ] 
               
               
                   
                 5426A &gt; G 
                   
                   
                   
                 GTAAGGAACAGCTCTCTCATATATT 
               
               
                   
               
               
                 21 
                 CNR1, c.−63- 
                 rs806379 
                 CNR1 
                 6 
                 GCAGAACTGATCTGAAATTAGATGA[   A/T   ] 
               
               
                   
                 6211T &gt; A 
                   
                   
                   
                 ATTAAATGCATGTAAAACATAGTGC 
               
               
                   
               
               
                 22 
                 CNR1, c.−63- 
                 rs6928499 
                 CNR1 
                 6 
                 TGAAATTAAATGCATGTAAAACATA[   C/G   ] 
               
               
                   
                 6233C &gt; G 
                   
                   
                   
                 TGCCTGACACAAAAGTAAGTCTTCA 
               
               
                   
               
               
                 23 
                 COMT, 472G &gt; A 
                 rs4680 
                 COMT 
                 22 
                 CCAGCGGATGGTGGATTTCGCTGGC[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 TGAAGGACAAGGTGTGCATGCCTGA 
               
               
                   
               
               
                 24 
                 CREBBP, c.3837- 
                 rs3025684 
                 CREBBP 
                 16 
                 TCCTTGCAATCAACGAAACTAGGAG[   A/G   ] 
               
               
                   
                 8C &gt; T 
                   
                   
                   
                 CAAAGAAGGCGCACTGTTAAAGCAC 
               
               
                   
               
               
                 25 
                 CSNK1E, c.737- 
                 rs1534891 
                 CSNK1E 
                 22 
                 AGAGCCATGGCCTTCCCTATCCTAC[   C/T   ]G 
               
               
                   
                 160A &gt; G 
                   
                   
                   
                 TGATGAAAGCCTAGCCTGCCCGTG 
               
               
                   
               
               
                 26 
                 CSNK1E, c.77- 
                 rs6001093 
                 CSNK1E 
                 22 
                 ATTGCCTTATAGCCTTGGGGTTAGG[   C/T   ]A 
               
               
                   
                 2140G &gt; A 
                   
                   
                   
                 AAGCTTTTATTTTTATCCCTGATT 
               
               
                   
               
               
                 27 
                 CSNK1E, 
                 rs135745 
                 CSNK1E 
                 22 
                 ACTAGGCCTCTCACACTGGATTCTG[   C/G   ]A 
               
               
                   
                 g.38287631G &gt; C 
                   
                   
                   
                 TTGGGGTGAACCACTTGCTACTCT 
               
               
                   
               
               
                 28 
                 CYP1A2, *1C; L - 
                 rs2069514 
                 CYP1A2 
                 15 
                 TGGCTCACCGCAACCTCCGCCTCTC[   G/A   ]G 
               
               
                   
                 3860G &gt; A 
                   
                   
                   
                 ATTCAAGCAATTGTCATGCCCCAG 
               
               
                   
               
               
                 29 
                 CYP1A2, *1D; L; V; 
                 rs35694136 
                 CYP1A2 
                 15 
                 TGCAGTGAGCCATGATTGTGGCACA[   T/-   ]G 
               
               
                   
                 W −2467; −1635delT 
                   
                   
                   
                 AACCCCAACCTGGGTGACAGAGCA 
               
               
                   
               
               
                 30 
                 CYP1A2, *1F, K, 
                 rs762551 
                 CYP1A2 
                 15 
                 TGCTCAAAGGGTGAGCTCTGTGGGC[   C/A   ] 
               
               
                   
                 L; V; W + −163A &gt; C 
                   
                   
                   
                 CAGGACGCATGGTAGATGGAGCTTA 
               
               
                   
               
               
                 31 
                 CYP1A2, *1K - 
                 rs12720461 
                 CYP1A2 
                 15 
                 GGCTAGGTGTAGGGGTCCTGAGTTC[   C/T   ] 
               
               
                   
                 729C &gt; T 
                   
                   
                   
                 GGGCTTTGCTACCCAGCTCTTGACT 
               
               
                   
               
               
                 32 
                 CYP2B6, 
                 rs3745274 
                 CYP2B6 
                 19 
                 TCATGGACCCCACCTTCCTCTTCCA[   G/T   ]T 
               
               
                   
                 *13*6*7*9 + 516G &gt; T 
                   
                   
                   
                 CCATTACCGCCAACATCATCTGCT 
               
               
                   
               
               
                 33 
                 CYP2C19, *17*4B - 
                 rs12248560 
                 CYP2C19 
                 10 
                 AAATTTGTGTCTTCTGTTCTCAAAG[   C/T   ]A 
               
               
                   
                 806C &gt; T 
                   
                   
                   
                 TCTCTGATGTAAGAGATAATGCGC 
               
               
                   
               
               
                 34 
                 CYP2C19, *2 +  
                 rs4244285 
                 CYP2C19 
                 10 
                 TTCCCACTATCATTGATTATTTCCC[   A/G   ]G 
               
               
                   
                 681G &gt; A 
                   
                   
                   
                 GAACCCATAACAAATTACTTAAAA 
               
               
                   
               
               
                 35 
                 CYP2C19, *3 
                 rs4986893 
                 CYP2C19 
                 10 
                 ACATCAGGATTGTAAGCACCCCCTG[   A/G   ] 
               
               
                   
                 636G &gt; A 
                   
                   
                   
                 ATCCAGGTAAGGCCAAGTTTTTTGC 
               
               
                   
               
               
                 36 
                 CYP2C19, *4 1A &gt; G 
                 rs28399504 
                 CYP2C19 
                 10 
                 GTCTTAACAAGAGGAGAAGGCTTCA[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 TGGATCCTTTTGTGGTCCTTGTGCT 
               
               
                   
               
               
                 37 
                 CYP2C19, *5 
                 rs56337013 
                 CYP2C19 
                 10 
                 CCTATGTTTGTTATTTTCAGGAAAA[   C/T   ]G 
               
               
                   
                 1297C &gt; T 
                   
                   
                   
                 GATTTGTGTGGGAGAGGGCCTGGC 
               
               
                   
               
               
                 38 
                 CYP2C19, *6 
                 rs72552267 
                 CYP2C19 
                 10 
                 CGGCGTTTCTCCCTCATGACGCTGC[   A/G   ]G 
               
               
                   
                 395G &gt; A 
                   
                   
                   
                 AATTTTGGGATGGGGAAGAGGAGC 
               
               
                   
               
               
                 39 
                 CYP2C19, *7 
                 rs72558186 
                 CYP2C19 
                 10 
                 TGCTTCCTGATCAAAATGGAGAAGG[   A/T   ] 
               
               
                   
                 19294T &gt; A 
                   
                   
                   
                 AAAATGTTAACAAAAGCTTAGTTAT 
               
               
                   
               
               
                 40 
                 CYP2C19, *8 
                 rs41291556 
                 CYP2C19 
                 10 
                 AATCGTTTTCAGCAATGGAAAGAGA[   C/T   ] 
               
               
                   
                 358T &gt; C 
                   
                   
                   
                 GGAAGGAGATCCGGCGTTTCTCCCT 
               
               
                   
               
               
                 41 
                 CYP2C19, *9 
                 rs17884712 
                 CYP2C19 
                 10 
                 ATGGGGAAGAGGAGCATTGAGGACC[   A/G   ] 
               
               
                   
                 431G &gt; A 
                   
                   
                   
                 TGTTCAAGAGGAAGCCCGCTGCCTT 
               
               
                   
               
               
                 42 
                 CYP2C9, *11 
                 rs28371685 
                 CYP2C9 
                 10 
                 GATTGAACGTGTGATTGGCAGAAAC[   T/C   ] 
               
               
                   
                 1003C &gt; T 
                   
                   
                   
                 GGAGCCCCTGCATGCAAGACAGGAG 
               
               
                   
               
               
                 43 
                 CYP2C9, *2 +  
                 rs1799853 
                 CYP2C9 
                 10 
                 GATGGGGAAGAGGAGCATTGAGGAC[   C/T   ] 
               
               
                   
                 430C &gt; T 
                   
                   
                   
                 GTGTTCAAGAGGAAGCCCGCTGCCT 
               
               
                   
               
               
                 44 
                 CYP2C9, *3 +  
                 rs1057910 
                 CYP2C9 
                 10 
                 TGTGGTGCACGAGGTCCAGAGATAC[   C/A   ] 
               
               
                   
                 noamp*4*4 1075A &gt; C 
                   
                   
                   
                 TTGACCTTCTCCCCACCAGCCTGCC 
               
               
                   
               
               
                 45 
                 CYP2C9, *4 NOAMP 
                 rs56165452 
                 CYP2C9 
                 10 
                 GTGGTGCACGAGGTCCAGAGATACA[   C/T   ] 
               
               
                   
                 *3*3 1076T &gt; C 
                   
                   
                   
                 TGACCTTCTCCCCACCAGCCTGCCC 
               
               
                   
               
               
                 46 
                 CYP2C9, *5 
                 rs28371686 
                 CYP2C9 
                 10 
                 TGCACGAGGTCCAGAGATACATTGA[   C/G   ] 
               
               
                   
                 1080C &gt; G 
                   
                   
                   
                 CTTCTCCCCACCAGCCTGCCCCATG 
               
               
                   
               
               
                 47 
                 CYP2C9, *6 818delA 
                 rs9332131 
                 CYP2C9 
                 10 
                 TGATTGCTTCCTGATGAAAATGGAG[   -/A   ] 
               
               
                   
                   
                   
                   
                   
                 AGGTAAAATGTAAACAAAAGCTTAG 
               
               
                   
               
               
                 48 
                 CYP2D6, *12 
                 rs5030862 
                 CYP2D6 
                 22 
                 TCCACATGCAGCAGGTTGCCCAGCC[   C/T   ] 
               
               
                   
                 124G &gt; A 
                   
                   
                   
                 GGGCAGTGGCAGGGGGCCTGGTGGG 
               
               
                   
               
               
                 49 
                 CYP2D6, *14 NOAMP 
                 rs5030865 
                 CYP2D6 
                 22 
                 TTGTGCCCTTCTGCCCATCACCCAC[   T/C   ]G 
               
               
                   
                 *8*8 1758G &gt; A 
                   
                   
                   
                 GAGTGGTTGGCGAAGGCGGCACAA 
               
               
                   
               
               
                 50 
                 CYP2D6, *17*40 
                 rs28371706 
                 CYP2D6 
                 22 
                 ACGCGGCCCGAAACCCAGGATCTGG[   G/A   ] 
               
               
                   
                 1023C &gt; T 
                   
                   
                   
                 TGATGGGCACAGGCGGGCGGTCGGC 
               
               
                   
               
               
                 51 
                 CYP2D6,*2*4k*8*11 
                 rs16947 
                 CYP2D6 
                 22 
                 GAGAACAGGTCAGCCACCACTATGC[   A/G   ] 
               
               
                   
                 *14*17*29*41 + 2850 
                   
                   
                   
                 CAGGTTCTCATCATTGAAGCTGCTC 
               
               
                   
                 C &gt; T 
                   
                   
                   
                   
               
               
                   
               
               
                 52 
                 CYP2D6, *29 +  
                 rs59421388 
                 CYP2D6 
                 22 
                 TCTGGTCGCCGCACCTGCCCTATCA[   C/T   ]G 
               
               
                   
                 3183G &gt; A 
                   
                   
                   
                 TCGTCGATCTCCTGTTGGACACGG 
               
               
                   
               
               
                 53 
                 CYP2D6, *2A*35 + - 
                 rs1080985 
                 CYP2D6 
                 22 
                 TAATTTTGTATTTTTTGTAGAGACC[   G/C   ]G 
               
               
                   
                 1584C &gt; G 
                   
                   
                   
                 GTTCTTCCAAGTTGTCCAGGCTGG 
               
               
                   
               
               
                 54 
                 CYP2D6, *3 
                 rs35742686 
                 CYP2D6 
                 22 
                 GGCTGGGCTGGGTCCCAGGTCATCC[   T/-   ]G 
               
               
                   
                 2549delA 
                   
                   
                   
                 TGCTCAGTTAGCAGCTCATCCAGC 
               
               
                   
               
               
                 55 
                 CYP2D6, *35 31G &gt; A 
                 rs769258 
                 CYP2D6 
                 22 
                 AGGAGCAGGAAGATGGCCACTATCA[   C/T   ] 
               
               
                   
                   
                   
                   
                   
                 GGCCAGGGGCACCAGTGCTTCTAGC 
               
               
                   
               
               
                 56 
                 CYP2D6, *4 
                 rs3892097 
                 CYP2D6 
                 22 
                 AGACCGTTGGGGCGAAAGGGGCGTC[   C/T   ] 
               
               
                   
                 1846G &gt; A 
                   
                   
                   
                 TGGGGGTGGGAGATGCGGGTAAGGG 
               
               
                   
               
               
                 57 
                 CYP2D6, *4*10*14A + 
                 rs1065852 
                 CYP2D6 
                 22 
                 CCGGGCAGTGGCAGGGGGCCTGGTG[   A/G   ] 
               
               
                   
                 100C &gt; T not*4M 
                   
                   
                   
                 GTAGCGTGCAGCCCAGCGTTGGCGC 
               
               
                   
               
               
                 58 
                 CYP2D6, *41 +  
                 rs28371725 
                 CYP2D6 
                 22 
                 TTCATGGGCCCCCGCCTGTACCCTT[   C/T   ]C 
               
               
                   
                 2988G &gt; A 
                   
                   
                   
                 TCCCTCGGCCCCTGCACTGTTTCC 
               
               
                   
               
               
                 59 
                 CYP2D6, *6 
                 rs5030655 
                 CYP2D6 
                 22 
                 AGGCAGGCGGCCTCCTCGGTCACCC[   A/-   ]C 
               
               
                   
                 1707delT 
                   
                   
                   
                 TGCTCCAGCGACTTCTTGCCCAGG 
               
               
                   
               
               
                 60 
                 CYP2D6, *7 
                 rs5030867 
                 CYP2D6 
                 22 
                 GATGGGCTCACGCTGCACATCCGGA[   G/T   ] 
               
               
                   
                 2935A &gt; C 
                   
                   
                   
                 GTAGGATCATGAGCAGGAGGCCCCA 
               
               
                   
               
               
                 61 
                 CYP2D6, *8NOAMP 
                 rs5030865 
                 CYP2D6 
                 22 
                 TTGTGCCCTTCTGCCCATCACCCAC[   A/C   ]G 
               
               
                   
                 *14*14 1758G &gt; T 
                   
                   
                   
                 GAGTGGTTGGCGAAGGCGGCACAA 
               
               
                   
               
               
                 62 
                 CYP2D6, *9 
                 rs5030656 
                 CYP2D6 
                 22 
                 CCCCACCGTGGCAGCCACTCTCAC[   CTT/-   ] 
               
               
                   
                 2613_2615delAGA 
                   
                   
                   
                 CTCCATCTCTGCCAGGAAGGCCTC 
               
               
                   
               
               
                 63 
                 CYP3A4, *12 
                 rs12721629 
                 CYP3A4 
                 7 
                 ACATCTTTTTTGCAGACCCTCTCAA[   A/G   ]T 
               
               
                   
                 1117C &gt; T 
                   
                   
                   
                 CTCATAGCAATTGGGAATAATCTG 
               
               
                   
               
               
                 64 
                 CYP3A4, *17 
                 rs4987161 
                 CYP3A4 
                 7 
                 GTTGAGAGAGTCGATGTTCACTCCA[   A/G   ] 
               
               
                   
                 566T &gt; C 
                   
                   
                   
                 ATGATGTGCTAGTGATCACATCCAT 
               
               
                   
               
               
                 65 
                 CYP3A4, *1B + - 
                 rs2740574 
                 CYP3A4 
                 7 
                 TAAAATCTATTAAATCGCCTCTCTC[   C/T   ]T 
               
               
                   
                 392A &gt; G 
                   
                   
                   
                 GCCCTTGTCTCTATGGCTGTCCTC 
               
               
                   
               
               
                 66 
                 CYP3A4, *2 664T &gt; C 
                 rs55785340 
                 CYP3A4 
                 7 
                 GAAATAGTAGTCCACATACTTATTG[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 GAGAAAGAATGGATCCAAAAAATCA 
               
               
                   
               
               
                 67 
                 CYP3A4, *22 intron6 
                   
                   
                   
                 GTGCCAGTGATGCAGCTGGCCCTAC[   G/A   ] 
               
               
                   
                 15389C &gt; T 
                 rs35599367 
                 CYP3A4 
                 7 
                 CTGGGTGTGATGGAGACACTGAACT 
               
               
                   
               
               
                 68 
                 CYP3A4, *3 
                 rs4986910 
                 CYP3A4 
                 7 
                 TTTCATGTTCATGAGAGCAAACCTC[   A/G   ]T 
               
               
                   
                 1334T &gt; C 
                   
                   
                   
                 GCCAATGCAGTTTCTGGGTCCACT 
               
               
                   
               
               
                 69 
                 CYP3A5, *2 
                 rs28365083 
                 CYP3A5 
                 7 
                 CTTTGGGTCATGGTGAAGAGCATAA[   G/T   ] 
               
               
                   
                 27289C &gt; A 
                   
                   
                   
                 TTGGAATCACCACCATTGACCCTTT 
               
               
                   
               
               
                 70 
                 CYP3A5, *3*10*1D 
                 rs15524 
                 CYP3A5 
                 7 
                 AGCTTTCTTGAAGACCAAAGTAGAA[   A/G   ] 
               
               
                   
                 31611C &gt; T 
                   
                   
                   
                 TCCTTAGAATAACTCATTCTCCACT 
               
               
                   
               
               
                 71 
                 CYP3A5, *3*9 
                 rs776746 
                 CYP3A5 
                 7 
                 ATGTGGTCCAAACAGGGAAGAGATA[   T/C   ] 
               
               
                   
                 6986A &gt; G 
                   
                   
                   
                 TGAAAGACAAAAGAGCTCTTTAAAG 
               
               
                   
               
               
                 72 
                 CYP3A5, *3B H30Y 
                 rs28383468 
                 CYP3A5 
                 7 
                 ATTCCCAGTCTCTTAAAAAGTCCAT[   G/A   ]T 
               
               
                   
                 3705C &gt; T 
                   
                   
                   
                 GTACGGGTCCCATATCTACAAAGT 
               
               
                   
               
               
                 73 
                 CYP3A5, *6 
                 rs10264272 
                 CYP3A5 
                 7 
                 CTAAGAAACCAAATTTTAGGAACTT[   C/T   ]T 
               
               
                   
                 14690G &gt; A 
                   
                   
                   
                 TAGTGCTCTCCACAAAGGGGTCTT 
               
               
                   
               
               
                 74 
                 CYP3A5, *7 
                 rs41303343 
                 CYP3A5 
                 7 
                 CCATCTGTACCACGGCATCATAGGT[   A/-   ]A 
               
               
                   
                 27131_27132insT 
                   
                   
                   
                 GGTGGTGCCTGGAAGGAAAGAAAC 
               
               
                   
               
               
                 75 
                 CYP3A5, *8 
                 rs55817950 
                 CYP3A5 
                 7 
                 AGTCTCTTAAAAAGTCCATGTGTAC[   A/G   ]G 
               
               
                   
                 3699C &gt; T 
                   
                   
                   
                 GTCCCATATCTACAAAGTGAAACA 
               
               
                   
               
               
                 76 
                 CYP3A5, *9 
                 rs28383479 
                 CYP3A5 
                 7 
                 CCCCTCACCTTATTGGGCAAAACTG[   C/T   ]A 
               
               
                   
                 19386G &gt; A 
                   
                   
                   
                 TCAATCTCCTTTTGCAGTTTCTGC 
               
               
                   
               
               
                 77 
                 DBH, c.−979T &gt; C 
                 rs1611115 
                 DBH 
                 9 
                 AAGGCAGCTGCCCTCAGTCTACTTG[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 GGAGAGGACAGGAGGGAGAGGTGC 
               
               
                   
               
               
                 78 
                 DBI, c.− 
                 rs12613135 
                 DBI 
                 2 
                 CATAAACAGAGCTGAGGATCTTGCA[   C/T   ] 
               
               
                   
                 216 + 1593A &gt; G 
                   
                   
                   
                 TCTCAGAATTATGAAAAGCAATATT 
               
               
                   
               
               
                 79 
                 DCC, c.*2140T &gt; C 
                 rs2292043 
                 DCC 
                 18 
                 AGATTTTAGGGATTGAGTCACACCT[   T/C   ]C 
               
               
                   
                   
                   
                   
                   
                 AATCTATAGAATGAAGTTGACCAA 
               
               
                   
               
               
                 80 
                 DCC, c.*3949T &gt; C 
                 rs12607853 
                 DCC 
                 18 
                 TACAGAAAAGCTTTTTATTTGAGTC[   C/T   ]A 
               
               
                   
                   
                   
                   
                   
                 GTGTTTAAAATTAAATTGGATACT 
               
               
                   
               
               
                 81 
                 DCC, c.*4376T &gt; C 
                 rs16956878 
                 DCC 
                 18 
                 GGGCATGGGCCAAGGGATCTCACTG[   C/T   ] 
               
               
                   
                   
                   
                   
                   
                 GTGCTGAACATGTATTTTCAGATGC 
               
               
                   
               
               
                 82 
                 DRD2, 
                 rs2075652 
                 DRD2 
                 11 
                 GCACTTAGTAAGCACTTTACAAATG[   G/A   ]T 
               
               
                   
                 c.285 + 191C &gt; T 
                   
                   
                   
                 AGTTGGGATTATTAAGGAAACAAT 
               
               
                   
               
               
                 83 
                 DRD2, 
                 rs2734833 
                 DRD2 
                 11 
                 TCCTTCCTCTTTATCCCAAGGGGGC[   G/A   ]G 
               
               
                   
                 c.285 + 2169C &gt; T 
                   
                   
                   
                 TGAATAGGAAAGACAGAGTCCTCC 
               
               
                   
               
               
                 84 
                 DRD2, c.−31- 
                 rs4436578 
                 DRD2 
                 11 
                 TCACACTGCTGGAAACCTCCGGAAG[   C/T   ] 
               
               
                   
                 11361G &gt; A 
                   
                   
                   
                 CCTTGTCCCCACGTTTCTCATCCTT 
               
               
                   
               
               
                 85 
                 DRD2, c.−31- 
                 rs1079596 
                 DRD2 
                 11 
                 CCAAAAATGTAGGGTATGGCAGTAA[   C/T   ] 
               
               
                   
                 1215G &gt; A 
                   
                   
                   
                 GTTGAGGATAATTAAACTGCAGGGA 
               
               
                   
               
               
                 86 
                 DRD2, c.−31- 
                 rs17115583 
                 DRD2 
                 11 
                 GGAATTGAAGAAGGTGTGTCAATGC[   A/G   ] 
               
               
                   
                 13498C &gt; T 
                   
                   
                   
                 TCCTATTTTTATTGTTTTTTTTTTA 
               
               
                   
               
               
                 87 
                 DRD2, c.−31- 
                 rs11214607 
                 DRD2 
                 11 
                 GGTAGCCTATGGACCACATTTAGCT[   G/T   ]G 
               
               
                   
                 16735A &gt; C 
                   
                   
                   
                 CATACAGGATTTGTTGGGCTCACA 
               
               
                   
               
               
                 88 
                 DRD2, c.−31- 
                 rs1125394 
                 DRD2 
                 11 
                 AATTAAACTTATCAGCATTCCAAGG[   C/T   ]G 
               
               
                   
                 1781A &gt; G 
                   
                   
                   
                 TTTCATACAAAGCACATGACTTCC 
               
               
                   
               
               
                 89 
                 DRD2, c.−31-882G &gt; A 
                 rs1079597 
                 DRD2 
                 11 
                 GAACCACATGATCAGATTCGCCTTT[   C/T   ]G 
               
               
                   
                 Taq1B 
                   
                   
                   
                 AATAGGTGATTCTGACAGCACTGT 
               
               
                   
               
               
                 90 
                 DRD2, c.−585A &gt; G 
                 rs1799978 
                 DRD2 
                 11 
                 GCGCTCCCACCCACACCCAGAGTAA[   C/T   ] 
               
               
                   
                   
                   
                   
                   
                 AAGCTGTGATTGCAGGCTGGGTCCT 
               
               
                   
               
               
                 91 
                 DRD2, c.724- 
                 rs2283265 
                 DRD2 
                 11 
                 AGGAAACAGGCTCATAGAAGGTAAG[   A/C   ] 
               
               
                   
                 353G &gt; T 
                   
                   
                   
                 AACTTGCCTAAGGTCACTCAGCAAA 
               
               
                   
               
               
                 92 
                 DRD2, c.811-83G &gt; T 
                 rs1076560 
                 DRD2 
                 11 
                 CCCATCTCACTGGCCCCTCCCTTTC[   A/C   ]C 
               
               
                   
                   
                   
                   
                   
                 CCTCTGAAGACTCCTGCAAACACC 
               
               
                   
               
               
                 93 
                 DRD2, c.939T &gt; C 
                 rs6275 
                 DRD2 
                 11 
                 GGCTGTCGGGAGTGCTGTGGAGACC[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 TGGTGGGACGGGTCGGGGAGAGTCA 
               
               
                   
               
               
                 94 
                 DRD2, c.957C &gt; T 
                 rs6277 
                 DRD2 
                 11 
                 TCTTCTCTGGTTTGGCGGGGCTGT[   A/G   ]G 
               
               
                   
                   
                   
                   
                   
                 GAGTGCTGTGGAGACCATGGTGGG 
               
               
                   
               
               
                 95 
                 DRD3, c.−155- 
                 rs9825563 
                 DRD3 
                 3 
                 AATAGAAGAGAAGCAGGGTAAATGA[   A/G   ] 
               
               
                   
                 2597T &gt; C 
                   
                   
                   
                 GTGATCCTTTCTCTCTGGACTTCAC 
               
               
                   
               
               
                 96 
                 DRD3, c.25G &gt; A 
                 rs6280 
                 DRD3 
                 3 
                 GCCCCACAGGTGTAGTTCAGGTGGC[   C/T   ] 
               
               
                   
                   
                   
                   
                   
                 ACTCAGCTGGCTCAGAGATGCCATA 
               
               
                   
               
               
                 97 
                 DRD3, c.271- 
                 rs324029 
                 DRD3 
                 3 
                 ATAGGGAAGTGTTAGGTGAGGAGGG[   A/G   ] 
               
               
                   
                 2909T &gt; C 
                   
                   
                   
                 TAGTTGTTGGAAAAGGGATGGAAGT 
               
               
                   
               
               
                 98 
                 DRD3, c.527-630T &gt; C 
                 rs9288993 
                 DRD3 
                 3 
                 AAAAGGCAGGTAATGATATTGTGAC[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 TGGAGAATGTGCACTTAGAAGGGTC 
               
               
                   
               
               
                 99 
                 DRD3, 
                 rs2654754 
                 DRD3 
                 3 
                 CTCTGTCCATGTGTGTTCCCTTGAC[   A/G   ]T 
               
               
                   
                 c.723 + 2551C &gt; T 
                   
                   
                   
                 CTGTTTCCTCTAATGCAGGTGGCC 
               
               
                   
               
               
                 100 
                 DRD4, c.−521T &gt; C 
                 rs1800955 
                 DRD4 
                 11 
                 GGGCAGGGGGAGCGGGCGTGGAGGG[   C/T   ] 
               
               
                   
                   
                   
                   
                   
                 GCGCACGAGGTCGAGGCGAGTCCGC 
               
               
                   
               
               
                 101 
                 EXOC4, c.1183- 
                 rs718656 
                 EXOC4 
                 7 
                 GGAGATAGAATTTGCTCTTGCTATT[   C/T   ]A 
               
               
                   
                 39230C &gt; T 
                   
                   
                   
                 TTTCAAGAAATTGGTGATCTTGCA 
               
               
                   
               
               
                 102 
                 FAAH, 
                 rs2295633 
                 FAAH 
                 1 
                 GATGTTGTCGTCGGGGTGAACTGTG[   A/G   ] 
               
               
                   
                 c.1077 + 127A &gt; G 
                   
                   
                   
                 CCCTGTGGGACAAGTATATAGAGGG 
               
               
                   
               
               
                 103 
                 FAAH, c.196- 
                 rs3766246 
                 FAAH 
                 1 
                 AAAGAATATATCAAGAGGATTATCT[   A/G   ] 
               
               
                   
                 2092A &gt; G 
                   
                   
                   
                 GTGTGTTTGGGGAGAAGTCTTGAAC 
               
               
                   
               
               
                 104 
                 FAAH, c.385C &gt; A 
                 rs324420 
                 FAAH 
                 1 
                 CTGTGAGACTCAGCTGTCTCAGGC[   A/C   ]C 
               
               
                   
                   
                   
                   
                   
                 AAGGCAGGGCCTGCTCTATGGCGT 
               
               
                   
               
               
                 105 
                 FSTL4, c.161- 
                 rs31347 
                 FSTL4 
                 5 
                 CATCCAAATGCTGACATGGCAAGGA[   C/T   ] 
               
               
                   
                 71797G &gt; A 
                   
                   
                   
                 ATCTTGGTCATCAAGTCTAACCCCA 
               
               
                   
               
               
                 106 
                 GABRB3, c.− 
                 rs4906902 
                 GABRB3 
                 15 
                 TCACGTTGGCATGTTTCTGTGCATT[   A/G   ]A 
               
               
                   
                 1659T &gt; C 
                   
                   
                   
                 TTTTAAATATACTGCCTTTTTAAA 
               
               
                   
               
               
                 107 
                 GABRB3, c.249- 
                 rs7165224 
                 GABRB3 
                 15 
                 TCTTCTTATTTTTCTTCTGTTCTCC[   T/C   ]TC 
               
               
                   
                 6417A &gt; G 
                   
                   
                   
                 CCCTCCCCTCTCTTCCTTTTCTT 
               
               
                   
               
               
                 108 
                 GAD1, 
                 rs2058725 
                 GAD1 
                 2 
                 CAGAGAGATGAGAACTACATCATTT[   C/T   ] 
               
               
                   
                 c.547 + 2419T &gt; C 
                   
                   
                   
                 ATTATGAAAGCCCAGAATGGCGTTG 
               
               
                   
               
               
                 109 
                 GAD1, c.− 
                 rs1978340 
                 GAD1 
                 2 
                 CACCTTGACTGACCACGTTTTAGGC[   A/G   ]T 
               
               
                   
                 64 + 189G &gt; A 
                   
                   
                   
                 GAAGATCTCCCCGCAGCCCGTTTG 
               
               
                   
               
               
                 110 
                 GAL, c.−1998C &gt; T 
                 rs948854 
                 GAL 
                 11 
                 CACAGGAACGTGCCCTCTGCTCCTC[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 CCTCTCGGCTGTCCTTCTGCCCAC 
               
               
                   
               
               
                 111 
                 GAL, c.82-77G &gt; A 
                 rs694066 
                 GAL 
                 11 
                 ATTGTTCTAAGTCCTCTGCCATGCC[   A/G   ]G 
               
               
                   
                   
                   
                   
                   
                 GAAAGCCTGGGTGCACCCATTCAG 
               
               
                   
               
               
                 112 
                 GR1K1, 
                 rs2832407 
                 GR1K1 
                 21 
                 ATCAAGATCAGAAAGTTACAACCCT[   A/C   ] 
               
               
                   
                 c.1251 + 1338G &gt; T 
                   
                   
                   
                 GGGAGTGTGTGTGGCTCTTGCAGTT 
               
               
                   
               
               
                 113 
                 GRIN3A, 
                 rs17189632 
                 GRIN3A 
                 9 
                 GTTTCCTGCTGCGCACTTCCCCTGA[   A/T   ]A 
               
               
                   
                 c.2766 + 7656A &gt; T 
                   
                   
                   
                 ATAAAATCACTGGAGAGTTTAATG 
               
               
                   
               
               
                 114 
                 GRIN3B, c.1730C &gt; T 
                 rs2240158 
                 GRIN3B 
                 19 
                 TTTATGTGGCCCCTGCACTGGTCCA[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 TGGCTGGGCGTCTTTGCGGCCCTG 
               
               
                   
               
               
                 115 
                 HRPT2, c.1155- 
                 rs1408830 
                 HRPT2 
                 1 
                 GCACAAAATAGTGATGGCAATTCCT[   A/G   ] 
               
               
                   
                 4716A &gt; G 
                   
                   
                   
                 GTTTCATCAGTTCTGTGAGATATGT 
               
               
                   
               
               
                 116 
                 HTR2A, c.−998G &gt; A, 
                 rs6311 
                 HTR2A 
                 13 
                 ATGTCCTCGGAGTGCTGTGAGTGTC[   C/T   ]G 
               
               
                   
                 C &gt; T 
                   
                   
                   
                 GCACTTCCATCCAAAGCCAACAGT 
               
               
                   
               
               
                 117 
                 HTR2A, c.102C &gt; T, 
                 rs6313 
                 HTR2A 
                 13 
                 ATGCATCAGAAGTGTTAGCTTCTCC[   A/G   ]G 
               
               
                   
                 G &gt; A 
                   
                   
                   
                 AGTTAAAGTCATTACTGTAGAGCC 
               
               
                   
               
               
                 118 
                 HTR2C, −759C &gt; T 
                 rs3813929 
                 HTR2C 
                 X 
                 CTGCTCTTGGCTCCTCCCCTCATCC[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 CTTTTGGCCCAAGAGCGTGGTGCA 
               
               
                   
               
               
                 119 
                 HTR3B, c.*797T &gt; A 
                 rs1185027 
                 HTR3B 
                 11 
                 GTCAGCACAGGTTATTATTCACTTG[   A/T   ]T 
               
               
                   
                   
                   
                   
                   
                 GTGATTCCCATGGTCAACCTGGTA 
               
               
                   
               
               
                 120 
                 HTR3B, 
                 rs11606194 
                 HTR3B 
                 11 
                 AATTTGTTTATTAAAGCATCCTTTT[   T/C   ]CT 
               
               
                   
                 c.213 + 804T &gt; C 
                   
                   
                   
                 CCTATGTCTGAAAGATGGGCTGT 
               
               
                   
               
               
                 121 
                 HTR3B, c.−381T &gt; C 
                 rs3758987 
                 HTR3B 
                 11 
                 TTAGTGTCCTGAATGTCAGCAAGAG[   C/T   ] 
               
               
                   
                   
                   
                   
                   
                 ACTGCCTTAGGTAAAGGCTGTAAAG 
               
               
                   
               
               
                 122 
                 intergenic, 
                 rs1986513 
                 intergenic 
                 4 
                 CTGTTCATGATTATGCTTAGTTTTA[   A/T   ]CT 
               
               
                   
                 g.125146073A &gt; T 
                   
                   
                   
                 CCACAGAATTGTTGCTGTGTTTC 
               
               
                   
               
               
                 123 
                 intergenic, 
                 rs10494334 
                 intergenic 
                 1 
                 TTAGTAGACTTGAATTATAGATGCC[   A/G   ]C 
               
               
                   
                 g.163535374G &gt; A 
                   
                   
                   
                 AACTCTCATTCATGTGCATTTCTG 
               
               
                   
               
               
                 124 
                 intergenic, 
                 rs966162 
                 intergenic 
                 12 
                 CAGTCTCCTAAGACTTCACCCTAAC[   C/G   ]T 
               
               
                   
                 g.18873522C &gt; G 
                   
                   
                   
                 TTTATTCAAGCCATCAGCTACCAA 
               
               
                   
               
               
                 125 
                 intergenic, 
                 rs965972 
                 intergenic 
                 1 
                 TTGTTAGGATTCACATTTAAGTGAC[   A/G   ]T 
               
               
                   
                 g.193494720G &gt; A 
                   
                   
                   
                 AAAAACTGAGAAGAGTTAAGCGGC 
               
               
                   
               
               
                 126 
                 intergenic, 
                 rs952985 
                 intergenic 
                 7 
                 CATCAATTCAGCTGCAGTATCTTCA[   G/T   ]T 
               
               
                   
                 g.9757835G &gt; T 
                   
                   
                   
                 TCTTACAGTGGGGAAGCCAGAATC 
               
               
                   
               
               
                 127 
                 KCNC1, c.*1934A &gt; C 
                 rs60349741 
                 KCNC1 
                 11 
                 ATGTGTTTGTTCAGACATGCACACC[   A/C   ]G 
               
               
                   
                   
                   
                   
                   
                 CTAATCCCAGGACACAAAACCTGT 
               
               
                   
               
               
                 128 
                 LINC01456, 
                 rs2213602 
                 LINC01456 
                 X 
                 TCTAAGTGCTTTACAAACGTTGTTA[   A/G   ]C 
               
               
                   
                 g.18089955A &gt; G 
                   
                   
                   
                 TCATTTCACCCTTGCAACCATACG 
               
               
                   
               
               
                 129 
                 IVIPDZ, c.184- 
                 rs1389752 
                 IVIPDZ 
                 9 
                 TAGCTCCTGAACTAAATGAGACACA[   A/T   ] 
               
               
                   
                 10705T &gt; A 
                   
                   
                   
                 AATGGAGCAATAAGTTATAAGAAGG 
               
               
                   
               
               
                 130 
                 MTHFR, 1298A &gt; C 
                 rs1801131 
                 MTHFR 
                 1 
                 AAGAACGAAGACTTCAAAGACACTT[   G/T   ] 
               
               
                   
                   
                   
                   
                   
                 CTTCACTGGTCAGCTCCTCCCCCCA 
               
               
                   
               
               
                 131 
                 MTHFR, 677C &gt; T 
                 rs1801133 
                 MTHFR 
                 1 
                 GAAAAGCTGCGTGATGATGAAATCG[   G/A   ] 
               
               
                   
                   
                   
                   
                   
                 CTCCCGCAGACACCTTCTCCTTCAA 
               
               
                   
               
               
                 132 
                 NFKB1, c.119- 
                 rs230530 
                 NFKB 1 
                 4 
                 TTTTTAGCACCAAACATCTTAATTT[   A/G   ]C 
               
               
                   
                 1025A &gt; G 
                   
                   
                   
                 ATTCAAATAAATGAGAACCACCAT 
               
               
                   
               
               
                 133 
                 NR4A2, 
                 rs1405735 
                 NR4A2 
                 2 
                 ATAGCAGCCCGAATAAACTAAGAGA[   C/G   ] 
               
               
                   
                 g.156377320C &gt; G 
                   
                   
                   
                 GATACAATTTTAAAAAACAAATCCA 
               
               
                   
               
               
                 134 
                 NRXN3, 
                 rs11624704 
                 NRXN3 
                 14 
                 TGTCCTCTGGGTATAATCTCACTTA[   A/C   ]C 
               
               
                   
                 c.757 + 21874A &gt; C 
                   
                   
                   
                 TTTACTCTGCAAATGCAATGTTGG 
               
               
                   
               
               
                 135 
                 NTSR1, c.715- 
                 rs3915568 
                 NTSR1 
                 20 
                 TGCCTTGGATGCATCAGGTGCACCG[   T/C   ] 
               
               
                   
                 16565T &gt; C 
                   
                   
                   
                 AGGGCTTTTGAAGGCTCCACGAGG 
               
               
                   
               
               
                 136 
                 OPRD1, *343G &gt; A 
                 rs4654327 
                 OPRD1 
                 1 
                 TTAAACAGGGCATCTCCAGGAAGGC[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 GGGCTTCAACCTTGAGACAGCTTCG 
               
               
                   
               
               
                 137 
                 OPRD1, 
                 rs6669447 
                 OPRD1 
                 1 
                 CTCCTTCCCCCTTGCCTGGCAGATG[   C/T   ]C 
               
               
                   
                 c.227 + 10239T &gt; C 
                   
                   
                   
                 TGGACTTTGAGAGGCAGGGGGCTG 
               
               
                   
               
               
                 138 
                 OPRD1, 
                 rs2236857 
                 OPRD1 
                 1 
                 GAGGGTCCAACACTCAGACAGCATG[   C/T   ] 
               
               
                   
                 c.227 + 22487T &gt; C 
                   
                   
                   
                 CACTAGGTGTTTGTACAAAGGACCT 
               
               
                   
               
               
                 139 
                 OPRD1, 
                 rs678849 
                 OPRD1 
                 1 
                 GTCCTTCTTACCATAGTGTCAAAAG[   C/T   ]A 
               
               
                   
                 c.227 + 6066C &gt; T 
                   
                   
                   
                 CCTGCTAGGTGCTGAGCTTGGCTG 
               
               
                   
               
               
                 140 
                 OPRD1, 
                 rs2236861 
                 OPRD1 
                 1 
                 GGGCGGCAGAGCATCCGGAGTGGCC[   A/G   ] 
               
               
                   
                 c.227 + 634G &gt; A 
                   
                   
                   
                 TCGTCCCTGTGTTTGTGCAGCTGTG 
               
               
                   
               
               
                 141 
                 OPRD1, c.228- 
                 rs10753331 
                 OPRD1 
                 1 
                 GGAGTGATTAAATGAGGTGATCTCT[   A/G   ] 
               
               
                   
                 20884G &gt; A 
                   
                   
                   
                 TAAATGTCATAGTAGCATTCGATAG 
               
               
                   
               
               
                 142 
                 OPRD1, c.228- 
                 rs508448 
                 OPRD1 
                 1 
                 AAGGGTACAGCAGGGAACAAAATGG[   A/G   ] 
               
               
                   
                 3941A &gt; G 
                   
                   
                   
                 1CGAAGTCTTCTGGCTTCAGGGAACT 
               
               
                   
               
               
                 143 
                 OPRD1, c.80G &gt; T 
                 rs1042114 
                 OPRD1 
                 1 
                 GCCTCGGACGCCTACCCTAGCGCCT[   G/T   ]C 
               
               
                   
                   
                   
                   
                   
                 CCCAGCGCTGGCGCCAATGCGTCG 
               
               
                   
               
               
                 144 
                 OPRD1, c.921C &gt; T 
                 rs2234918 
                 OPRD 1 
                 1 
                 CGCTGCACCTGTGCATCGCGCTGGG[   C/T   ]T 
               
               
                   
                   
                   
                   
                   
                 ACGCCAATAGCAGCCTCAACCCCG 
               
               
                   
               
               
                 145 
                 OPRK1, c.258- 
                 rs6473797 
                 OPRK1 
                 8 
                 AAAACACAAGTGTGATCAAATGCCA[   C/T   ] 
               
               
                   
                 5311A &gt; G 
                   
                   
                   
                 GGACCCACAGGAAGCTGGTGGCTCT 
               
               
                   
               
               
                 146 
                 OPRK1, c.36G &gt; T 
                 rs1051660 
                 OPRK1 
                 8 
                 AGGCGCTCGGGGCGCAGGTAGGGCC[   A/C   ] 
               
               
                   
                   
                   
                   
                   
                 GGCTCCCCGCGGAAGATCTGGATCG 
               
               
                   
               
               
                 147 
                 OPRM, 
                 rs9479757 
                 OPRM 
                 6 
                 TGATGTTACCAGCCTGAGGGAAGGA[   A/G   ] 
               
               
                   
                 c.643 + 31G &gt; A 
                   
                   
                   
                 GGTTCACAGCCTGATATGTTGGTGA 
               
               
                   
               
               
                 148 
                 OPRM1, c.1- 
                 rs1074287 
                 OPRM1 
                 6 
                 TGGTATTCTATTGTACTGTGGCTGA[   A/G   ]G 
               
               
                   
                 11487A &gt; G 
                   
                   
                   
                 TAGTACTCAAACCACAAAATGCAG 
               
               
                   
               
               
                 149 
                 OPRM1, 
                 rs510769 
                 OPRM1 
                 6 
                 TGGTGTTGATGTGTATATTCAAATA[   C/T   ]T 
               
               
                   
                 c.290 + 1050C &gt; T 
                   
                   
                   
                 ACATGTGAATGTGAAATGCCATAT 
               
               
                   
               
               
                 150 
                 OPRM1, c .291- 
                 rs1381376 
                 OPRM1 
                 6 
                 GGAGAGGGATAAAAATGAGAATCAA[   C/T   ] 
               
               
                   
                 17703 C &gt; T 
                   
                   
                   
                 GTGGGAATGGTAAGATAACAAGAGC 
               
               
                   
               
               
                 151 
                 OPRM1, c.291- 
                 rs563649 
                 OPRM1 
                 6 
                 TTAGATCATGCAGGTCTATAACCAA[   C/T   ]G 
               
               
                   
                 2994C &gt; T 
                   
                   
                   
                 GTGAATCTAGCAAAAGTTATTTTC 
               
               
                   
               
               
                 152 
                 OPRM1, c.644- 
                 rs2075572 
                 OPRM1 
                 6 
                 GTTAGCTCTGGTCAAGGCTAAAAAT[   C/G   ] 
               
               
                   
                 83 G &gt; C 
                   
                   
                   
                 AATGAGCAAAATGGCAGTATTAACA 
               
               
                   
               
               
                 153 
                 OPRM1, 
                 rs6848893 
                 OPRM1 
                 4 
                 CTGGAAGAAAGTAACAGAAGATAAG[   C/T   ] 
               
               
                   
                 g.180916588C &gt; T 
                   
                   
                   
                 GGGGTGAGAGTGCTGGAGCAGTCAA 
               
               
                   
               
               
                 154 
                 OPRM1, 118A &gt; G 
                 rs1799971 
                 OPRM1 
                 6 
                 GGTCAACTTGTCCCACTTAGATGGC[   A/G   ]A 
               
               
                   
                   
                   
                   
                   
                 CCTGTCCGACCCATGCGGTCCGAA 
               
               
                   
               
               
                 155 
                 PDYN, c.*1030C &gt; T 
                 rs2235749 
                 PDYN 
                 20 
                 GAGTCCCTTACCCAATGCCCAGTGC[   A/G   ]T 
               
               
                   
                   
                   
                   
                   
                 ATGTTGGGCCAGATGGCTTGGACT 
               
               
                   
               
               
                 156 
                 PDYN, c.*743T &gt; C 
                 rs910080 
                 PDYN 
                 20 
                 TTTTCACTCCCTTCTGTAAGGAGTT[   A/G   ]G 
               
               
                   
                   
                   
                   
                   
                 GCACTGTCCAGGGTACCAACATGA 
               
               
                   
               
               
                 157 
                 PDYN, c.−321A &gt; G 
                 rs1997794 
                 PDYN 
                 20 
                 CCCTTCAACTCGAACTCCCTGGGCC[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 ACACAATAGGCTTCTCTTCGTGAC 
               
               
                   
               
               
                 158 
                 PDYN, 
                 rs1022563 
                 PDYN 
                 20 
                 CATCCACCACTACCACTGGCAGTGT[   C/T   ]T 
               
               
                   
                 g.1973693C &gt; T 
                   
                   
                   
                 GAGAGTCCTGATGCCTGTGGCTGT 
               
               
                   
               
               
                 159 
                 PENK, c.−1973A &gt; G 
                 rs2609997 
                 PENK 
                 8 
                 TGTATCCAATCCACCTATGCATCTA[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 TCTCCTAGACCTAGGGGGAAACCA 
               
               
                   
               
               
                 160 
                 RGS9-2, c.−2050G &gt; A 
                 rs1530351 
                 RGS9-2 
                 17 
                 TGGATGGATCTCTGCAGGGTCCAGC[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 TCCTCTAAATTGGAGGCTCTGAATC 
               
               
                   
               
               
                 161 
                 SCN9A, c.3448C &gt; T 
                 rs6746030 
                 SCN9A 
                 2 
                 TTAACTTGGCAGCATGAGAACCTCC[   A/G   ]T 
               
               
                   
                   
                   
                   
                   
                 ACACAACCTGACAAGAAAGACATG 
               
               
                   
               
               
                 162 
                 SLC6A3, c.−972T &gt; C 
                 rs2652511 
                 SLC6A3 
                 5 
                 CAGCGCGCGGAGGAATGGAGCCCCC[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 GGCCGCCAAGGCCCAGGATGTCCAG 
               
               
                   
               
               
                 163 
                 SLCO1B1, *1B 
                 rs2306283 
                 SLCO1B1 
                 12 
                 CAGGTATTCTAAAGAAACTAATATC[   A/G   ] 
               
               
                   
                 388A &gt; G 
                   
                   
                   
                 ATTCATCAGAAAATTCAACATCGAC 
               
               
                   
               
               
                 164 
                 SLCO1B1, *5 
                 rs4149056 
                 SLCO1B 1 
                 12 
                 TCTGGGTCATACATGTGGATATATG[   C/T   ]G 
               
               
                   
                 521T &gt; C 
                   
                   
                   
                 TTCATGGGTAATATGCTTCGTGGA 
               
               
                   
               
               
                 165 
                 SORCS3, c.628- 
                 rs728453 
                 SORCS3 
                 10 
                 ACTGTCTTTGTCATTCCTGATCAGC[   A/G   ]T 
               
               
                   
                 28349A &gt; G 
                   
                   
                   
                 GCCTCTGTGCCTTCATAGACGTTG 
               
               
                   
               
               
                 166 
                 TACR1, c.333T &gt; C 
                 rs6715729 
                 TACR1 
                 2 
                 TACTGGCGAAGACAGCGGCGATGGG[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 AAGAAGTTGTGGAACTTGCAGTAGA 
               
               
                   
               
               
                 167 
                 TACR1, c.390- 
                 rs735668 
                 TACR1 
                 2 
                 ACCTCCCCTATATTCTCCCCTCTCC[   A/C   ]TT 
               
               
                   
                 15150T &gt; G 
                   
                   
                   
                 TCGCATTCTGTTTCACCATCGTT 
               
               
                   
               
               
                 168 
                 TACR1, 
                 rs6741029 
                 TACR1 
                 2 
                 AACTCCAAAACACACACTCTTCTAA[   G/T   ]T 
               
               
                   
                 c.584 + 2505A &gt; C 
                   
                   
                   
                 ATTATACTGCCTCAAAACAAGTTT 
               
               
                   
               
               
                 169 
                 TACR3, 
                 rs1384401 
                 TACR3 
                 4 
                 GATAACCCATAGAGAACCTTTTTCA[   A/G   ] 
               
               
                   
                 c.888 + 12273C &gt; T 
                   
                   
                   
                 ATGATTGCCAAACACTGAAAGGCTT 
               
               
                   
               
               
                 170 
                 TACR3, 
                 rs4530637 
                 TACR3 
                 4 
                 TAGTCAGTGTGGGTCCTGAGGTTGT[   A/G   ]G 
               
               
                   
                 g.103585232A &gt; G 
                   
                   
                   
                 CATGTTTAGCAAAGTTACAGAACA 
               
               
                   
               
               
                 171 
                 TAOK3, 
                 rs795484 
                 TAOK3 
                 12 
                 AGACATGCGTGCCTTGGTGTTTCGG[   C/T   ]C 
               
               
                   
                 c.2535 + 170A &gt; G 
                   
                   
                   
                 TGTAGAAGGGGGACAATGCCTACC 
               
               
                   
               
               
                 172 
                 UGT2B7, c.−161T &gt; C 
                 rs7668258 
                 UGT2B7 
                 4 
                 CAGATCATTTACCTTCATTTGTCTC[   C/T   ]TT 
               
               
                   
                   
                   
                   
                   
                 GCCATCCACATGCTCAGACTGTT 
               
               
                   
               
               
                 173 
                 UGT2B7, c.−327A &gt; G 
                 rs7662029 
                 UGT2B7 
                 4 
                 TTGTGTCAAATGGACTGCAGAAACA[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 GATCTGTCACTGCTACTGTTCTGGA 
               
               
                   
               
               
                 174 
                 UGT2B7, c.−900G &gt; A 
                 rs7438135 
                 UGT2B7 
                 4 
                 CCAAATAACTGTGAGGAAGTGAGTC[   A/G   ] 
               
               
                   
                   
                   
                   
                   
                 GAGAACAAGCTAACCTAATGATTAA 
               
               
                   
               
               
                 175 
                 VKORC1, *2 - 
                 rs9923231 
                 VKORC1 
                 16 
                 GATTATAGGCGTGAGCCACCGCACC[   C/T   ] 
               
               
                   
                 1639G &gt; A 
                   
                   
                   
                 GGCCAATGGTTGTTTTTCAGGTCTT 
               
               
                   
               
               
                 176 
                 WLS, c.107-301T &gt; G 
                 rs1036066 
                 WLS 
                 1 
                 CTTCAAAACAATGTCACAAAAAATC[   A/C   ] 
               
               
                   
                   
                   
                   
                   
                 ACTGTGCTACAGTTCCCACCTGATT 
               
               
                   
               
               
                 177 
                 WLS, c.1393G &gt; A 
                 rs983034 
                 WLS 
                 1 
                 AAGGCACTGTTCACTTGGACTGTGA[   C/T   ]G 
               
               
                   
                   
                   
                   
                   
                 CCGCCCCATTTCCAATGGCCTTCC 
               
               
                   
               
               
                 178 
                 WLS, c.432G &gt; A 
                 rs3748705 
                 WLS 
                 1 
                 GGGCCATTTCAGTCCACTCAGCAAA[   C/T   ] 
               
               
                   
                   
                   
                   
                   
                 GCGTCATCACGGTAAGCCAGGGAAA 
               
               
                   
               
               
                 179 
                 ZNF804A, 
                 rs7597593 
                 ZNF804A 
                 2 
                 ATTTATGAATTTAATTCATTAATGT[   C/T   ]G 
               
               
                   
                 c.111 + 69783T &gt; C 
                   
                   
                   
                 TAAATAGTATTGCCCGAGAATTGG 
               
               
                   
               
               
                 180 
                 ZNF804A, c.256- 
                 rs1344706 
                 ZNF804A 
                 2 
                 AGATATCCAAGAAGTTGATTCTGAT[   A/C   ] 
               
               
                   
                 19902A &gt; C 
                   
                   
                   
                 GTTTTTGATTCTTTGTTTCAGTGTT 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the plurality of pre-determined alleles used to determine a risk score for opioid use disorder and/or relapse comprise at least one allele selected from the group consisting of: chr11:113399438 of gene ANKK1; chr11:27643996 of gene BDNFOS/antiBDNF; chr1:224706393 of gene CNIH3; chr6:88150763 of gene CNR1; chr16:3745362 of gene CREBBP; chr22:38287631 of gene CSNK1E; chr11:113425897 of gene DRD2; chr11:113441417 of gene DRD2; chr11:113426463 of gene DRD2; chr11:113414814 of gene DRD2; chr11:113412966 of gene DRD2; chr11:113425564 of gene DRD2; chr3:114162776 of gene DRD3; chr3:114140326 of gene DRD3; chr11:636784 of gene DRD4; chr15:26774621 of gene GABRB3; chr19:1005231 of gene GABRB3; chr1:163535374 of gene intergenic g.163535374G; chr1:28855013 of gene OPRD1; chr1:28863085 of gene OPRD1; chr6:154040884 of gene OPRM1; chr8:56447926 of gene PENK; chr5:1446274 of gene SLC6A3; chr2:75198602 of gene TACR1; chr2:75135918 of gene TACR1; chr4:103643921 of gene TACR3; chr4:103585232 of gene TACR3; chr1:68194522 of gene WLS; chr2:184668853 of gene ZNF804A; and chr2:184913701 of gene ZNF804A. The sequences for this listed plurality of pre-determined alleles are provided in Table 25. 
     In some embodiments, the plurality of pre-determined alleles used to determine a risk score for opioid use disorder and/or relapse comprise at least one allele selected from the group consisting of: chr6:154039662 of gene OPRM1 118A&gt;G; chr19:41006936 of gene CYP2B6*13*6*7*9+516G&gt;T; chr22:42130692 of gene CYP2D6*4*10*1 4A+100C&gt;T; chr1:11796321 of gene MTHFR 677C&gt;T; CYP2C9 non EM (IM or PM); and chr7:99768693 of gene CYP3A4*22 intron6 15389C&gt;T. 
     Opioid Use Disorder Scoring 
     In some embodiments, a method for assessing whether a subject is at risk of opioid use disorder is provided. The method comprises: (1) obtaining a biological sample from a subject; (2) performing an allelic analysis on the biological sample to determine the presence of a plurality of pre-determined alleles, wherein the plurality of pre-determined alleles comprise one or more genomic targets selected from Table 1; (3) assigning a count for each of the alleles in the plurality of pre-determined alleles that was present in the biological sample; (4) determining a risk score based upon a total count using a SNP Model, wherein the risk score identifies a severity of the genetic predisposition to opioid addiction; and (5) administering a medical assisted treatment procedure based on the risk score identified in the subject. 
     In other embodiments, a method for assessing whether a subject is at risk of opioid use disorder is provided. The method comprises: (1) obtaining a biological sample from a subject; (2) performing an allelic analysis on the biological sample to determine the presence of a plurality of pre-determined alleles, wherein the plurality of pre-determined alleles comprise two or more genomic targets selected from Table 1; (3) assigning a count for each of the alleles in the plurality of pre-determined alleles that was present in the biological sample; (4) determining a risk score based upon a total count using a SNP Model, wherein the risk score identifies a severity of the genetic predisposition to opioid addiction; and (5) administering a medical assisted treatment procedure based on the risk score identified in the subject. 
     In determining the scoring strategy for opioid use disorder using SNPs, a mutation allele or wild type allele could be a risk allele. In addition, some SNPs need a single copy of the risk allele to elevate the risk of OUD, while other SNPs need two copies of the risk allele to elevate the risk of OUD. The OUD risk score modeling process, as used herein, includes the following steps: Step 1) identify risk alleles and the number needed to express the risk; Step 2) develop one or more risk score models to predict OUD; Step 3) Choose an accurate model based on area under the receiver operating characteristic curve (AUROC); and Step 4) determine clinically reasonable threshold points. 
     Upon determination of an OUD risk score using a plurality of risk alleles selected from Table 1, a medical assisted treatment procedure or patient therapy may then be provided to the patient. Patients determined to be at higher risk of OUD could receive reduced quantities of opioids dispensed and/or receive increased monitoring/more frequent visits with a healthcare professional. Conversely, patients determined to be at a lower risk of OUD may require less frequent monitoring and may be appropriate for receiving larger quantities of opioids between prescription fills. Additionally, patients determined to be at a higher risk of relapse may have justification for longer inpatient rehabilitation stays and/or longer intensive outpatient rehabilitation support. Conversely, patients determined to be at a lower risk of relapse may justify an earlier transition from inpatient rehabilitation to intensive outpatient rehabilitation. There may be additional benefit for patients to understand their own risks so as to have a better appreciation for the genetic basis of disease and empowerment over their own treatment decisions. 
     Step 1: Identifying Risk SNP and Allele 
     A set of logistic regressions was conducted to identify SNPs that are significantly associated with the diagnosis of an OUD. Each SNP was coded to have three levels: a) having two wild type copies, b) having one wild type copy and one mutation copy, and c) two mutation copies. Two sets of odds ratios (ORs) were calculated for each SNP. For the first odds ratio, the odds of having OUD between those with two wild type copies and those with one or more mutation copies were compared. For the second odds ratio, the odds of having OUD between those subjects having two mutation copies and those having one or more wild type copies were compared. An OR was determined to be significant if the p-value was 0.05 or less. Because the strength of association between certain SNPs and the OUD could be different between male and female, the analysis can be stratified by sex. As a result, 10 SNPs for female and 9 SNPs for male were identified as being significantly associated with OUD. A listing of those SNPs and their corresponding risk alleles are shown in Table 2 (female) and Table 3 (male). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 SNPs Significantly Associated with OUD in Females. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Risk 
                   
                 Odds 
                   
               
               
                   
                   
                 Risk 
                 Geno- 
                   
                 Ratio 
                   
               
               
                 Assay Name 
                 Gene Symbol 
                 Allele 
                 types 
                 NCBI SNP 
                 (OR) 
                 p-value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 BDNFOS/antiBDNF 
                 BDNFOS/ 
                 C 
                 T/C, 
                 rs11030096 
                 2.2 
                 0.016 
               
               
                 n305 + 3991T &gt; C 
                 antiBDNF 
                   
                 C/T, or 
                   
                   
                   
               
               
                   
                   
                   
                 C/C 
                   
                   
                   
               
               
                 DRD2 c-31- 
                 DRD2 
                 A 
                 G/A, 
                 rs1079596 
                 1.9 
                 0.040 
               
               
                 1215G &gt; A 
                   
                   
                 A/G, or 
                   
                   
                   
               
               
                   
                   
                   
                 A/A 
                   
                   
                   
               
               
                 DRD2 c-31- 
                 DRD2 
                 G 
                 A/G, 
                 rs1125394 
                 1.9 
                 0.040 
               
               
                 1781A &gt; G 
                   
                   
                 G/A, or 
                   
                   
                   
               
               
                   
                   
                   
                 G/G 
                   
                   
                   
               
               
                 DRD3 c527- 
                 DRD3 
                 C 
                 T/C, 
                 rs9288993 
                 4.7 
                 0.022 
               
               
                 630T &gt; C 
                   
                   
                 C/T, or 
                   
                   
                   
               
               
                   
                   
                   
                 C/C 
                   
                   
                   
               
               
                 GABRB3 c- 
                 GABRB3 
                 T 
                 T/T 
                 rs4906902 
                 2.0 
                 0.027 
               
               
                 1659T &gt; C 
                   
                   
                   
                   
                   
                   
               
               
                 OPRM1 
                 OPRM1 
                 C 
                 C/C 
                 rs510769 
                 1.7 
                 0.044 
               
               
                 c290 + 1050C &gt; T 
                   
                   
                   
                   
                   
                   
               
               
                 TACR1 aka 
                 TACR1 aka 
                 T 
                 T/T 
                 rs735668 
                 2.0 
                 0.032 
               
               
                 NK1R c390- 
                 NK1R 
                   
                   
                   
                   
                   
               
               
                 15150T &gt; G 
                   
                   
                   
                   
                   
                   
               
               
                 ZNF804A 
                 ZNF804A 
                 T 
                 T/T 
                 rs7597593 
                 2.5 
                 0.024 
               
               
                 c111 + 69783T &gt; C 
                   
                   
                   
                   
                   
                   
               
               
                 DRD3 
                 DRD3 
                 C 
                 C/T, 
                 rs2654754 
                 3.3 
                 0.030 
               
               
                 c723 + 2551C &gt; T 
                   
                   
                 T/C, or 
                   
                   
                   
               
               
                   
                   
                   
                 C/C 
                   
                   
                   
               
               
                 OPRM1 118A &gt; G 
                 OPRM1 
                 A 
                 A/A 
                 rs1799971 
                 2.8 
                 0.004 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 SNPs Significantly Associated with OUD in Males. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Risk 
                   
                   
                   
               
               
                   
                   
                 Risk 
                 Geno- 
                   
                   
                   
               
               
                 Assay Name 
                 Gene Symbol 
                 Allele 
                 type 
                 NCBI SNP 
                 OR 
                 p-value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 CNR1 c-63- 
                 CNR1 
                 A 
                 A/A 
                 rs2023239 
                 2.0 
                 0.029 
               
               
                 5426A &gt; G 
                   
                   
                   
                   
                   
                   
               
               
                 TACR3 aka 
                 TACR3 aka 
                 G 
                 A/G, 
                 rs4530637 
                 2.6 
                 0.050 
               
               
                 NK3R 
                 NK3R 
                   
                 G/A, or 
                   
                   
                   
               
               
                 g.103585232A &gt; G 
                   
                   
                 G/G 
                   
                   
                   
               
               
                 TACR3 aka 
                 TACR3 aka 
                 C 
                 C/T, 
                 rs1384401 
                 2.9 
                 0.049 
               
               
                 NK3R 
                 NK3R 
                   
                 T/C, or 
                   
                   
                   
               
               
                 c888 + 12273C &gt; T 
                   
                   
                 C/C 
                   
                   
                   
               
               
                 EXOC4 c1183- 
                 EXOC4 
                 T 
                 T/T 
                 rs718656 
                 1.9 
                 0.042 
               
               
                 39230C &gt; T 
                   
                   
                   
                   
                   
                   
               
               
                 DRD3 c271- 
                 DRD3 
                 T 
                 T/C, 
                 rs324029 
                 2.0 
                 0.035 
               
               
                 2909T &gt; C 
                   
                   
                 C/T, or 
                   
                   
                   
               
               
                   
                   
                   
                 T/T 
                   
                   
                   
               
               
                 DRD3 c25G &gt; A 
                 DRD3 
                 G 
                 G/A, 
                 rs6280 
                 2.5 
                 0.006 
               
               
                   
                   
                   
                 A/G, or 
                   
                   
                   
               
               
                   
                   
                   
                 G/G 
                   
                   
                   
               
               
                 CNR1 c-63- 
                 CNR1 
                 G 
                 G/G 
                 rs6928499 
                 2.0 
                 0.029 
               
               
                 6233C &gt; G 
                   
                   
                   
                   
                   
                   
               
               
                 CYP2B6*13*6*7*9 + 
                 CYP2B6 
                 G 
                 G/G 
                 rs3745274 
                 2.0 
                 0.034 
               
               
                 516 G &gt; T 
                   
                   
                   
                   
                   
                   
               
               
                 CYP2D6*4*10*14A + 
                 CYP2D6 
                 C 
                 C/C 
                 rs1065852 
                 3.3 
                 0.043 
               
               
                 100C &gt; T 
                   
                   
                   
                   
                   
                   
               
               
                 not*4M 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, the SNP Model may include determining a weighted algorithm based on the ORs of the 10 SNPs for female and 9 SNPs for male with p-values of 0.05 or less, as provided in Tables 2 and 3 above. The weighted algorithm may be further based on the genetic codes as well as clinical (phenotype) data utilizing a logistic regression separately between male and female SNPs. 
     In some embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele C+ of gene BDNFOS/antiBDNF (rs11030096) wherein C+ includes T/C, C/T, or C/C; 
     allele A+ of gene DRD2 (rs1079596) wherein G+ includes G/A, A/G, or A/A; 
     allele G+ of gene DRD2 (rs1125394) wherein G+ includes A/G, G/A, or G/G; 
     allele C+ of gene DRD3 (rs9288993) wherein C+ includes T/C, C/T, or C/C; 
     allele T/T of gene GABRB3 (rs4906902); 
     allele C/C of gene OPRM1 (rs510769); 
     allele T/T of gene TACR1 (rs735668); 
     allele T/T of gene ZNF804A (rs7597593); 
     allele C+ of gene DRD3 (rs2654754) wherein C+ includes C/T, T/C, or C/C; and/or allele A/A of gene OPRM1 (rs1799971). 
     In other embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele A/A of gene CNR1 (rs2023239); 
     allele G+ of gene TACR3 (rs4530637) wherein G+ includes A/G, G/A, or G/G; 
     allele C+ of gene TACR3 (rs1384401) wherein C+ includes C/T, T/C, or C/C; 
     allele T/T of gene EXOC4 (rs718656); 
     allele T+ of gene DRD3 (rs324029) wherein T+ includes T/C, C/T, or T/T; 
     allele G+ of gene DRD3 (rs6280) wherein G+ includes G/A, A/G, or G/G; 
     allele G/G of gene CNR1 (rs6928499); 
     allele G/G of gene CYPB6 (rs3745274); and/or 
     allele C/C of gene CYP2D6 (rs1065852). 
     In further embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele C/C of gene CNIH3 (rs1369846); 
     allele A/A of gene CNIH3 (rs1436171); 
     allele A/A of gene GRIN3A (rs17189632); 
     allele C+ of gene HTR3B (rs11606194) wherein C+ includes T/C, C/T, or C/C; 
     allele C/C of gene OPRD1 (rs2234918); 
     allele G/G of gene WLS (rs1036066); 
     allele G+ of gene intergenic (rs965972) wherein G+ includes G/A, A/G, or G/G; 
     allele C/C of gene MTHFR (rs1801133); and/or 
     allele G/G of gene MTHFR (rs1801133). 
     In some embodiments, the plurality of pre-determined alleles comprise at least one allele selected from the group consisting of: 
     allele T/T of gene DRD3 (rs9825563); 
     allele T/T of gene GAL (rs948854); 
     allele C+ of gene NR4A2 (rs1405735) wherein C+ includes C/G, G/C, or C/C; 
     allele A+ of gene OPRM (rs9479757) wherein A+ includes G/A, A/G, or A/A; and/or allele T+(A+) of gene CYP3A4 (rs35599367) wherein T+ includes C/T, T/C, or T/T and wherein A+ includes G/A, A/G, or A/A. 
     Step 2: OUD Risk Score Modeling 
     Model 1: Sex-stratified, count SNPs with appropriate number of risk allele copies. The OUD risk score was calculated as the sum of SNPs that had the risk alleles as identified above in Tables 2 and 3. For example, EXOC4 was not counted towards the risk score if the subject had C/T, because two copies of T are required in order it to be counted. Similarly, DRD3(rs6280) was counted only once if a subject had at least one copy of G, regardless of the number of copies. Female subjects can have a risk score ranging from 0 to 10 and male subjects can have a risk score ranging from 0 to 9. Table 4 shows the distribution of risk scores by OUD in male and female subjects. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Risk score distribution by OUD in Model 1. 
               
            
           
           
               
               
               
            
               
                   
                 Female 
                 Male 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Risk score 
                 OUD No 
                 OUD Yes 
                 Total 
                 OUD No 
                 OUD Yes 
                 Total 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 0 
                 3 
                 0 
                 3 
                 0 
                 0 
                 0 
               
               
                 1 
                 7 
                 1 
                 8 
                 1 
                 0 
                 1 
               
               
                 2 
                 26 
                 9 
                 35 
                 6 
                 1 
                 7 
               
               
                 3 
                 37 
                 15 
                 52 
                 3 
                 2 
                 5 
               
               
                 4 
                 28 
                 21 
                 49 
                 6 
                 10 
                 16 
               
               
                 5 
                 11 
                 24 
                 35 
                 22 
                 11 
                 33 
               
               
                 6 
                 6 
                 15 
                 21 
                 17 
                 23 
                 40 
               
               
                 7 
                 1 
                 6 
                 7 
                 13 
                 23 
                 36 
               
               
                 8 
                 0 
                 1 
                 1 
                 6 
                 22 
                 28 
               
               
                 9 
                 0 
                 1 
                 1 
                 2 
                 15 
                 17 
               
               
                 Total 
                 119 
                 93 
                 212 
                 76 
                 107 
                 183 
               
               
                   
               
            
           
         
       
     
     Model 2: Sex-stratified, count risk alleles, maximum 2 per SNP). In some embodiments, the OUD risk score was calculated as the sum of risk alleles. For example, if a subject had “C/T” for EXOC4, 1 was added towards the risk score. In other examples, if a subject had “T/T” for EXOC4, 2 was added towards the risk score because two risk alleles were present. Accordingly, with the possibility of having a maximum count of 2 per SNP, female subjects can have a risk score ranging from 0 to 20 and male subjects can have a risk score ranging from 0 to 18. The distribution of risk scores by OUD generated using SNP Model 2 are provided in Table 5. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 OUD Risk Score Distribution using Model 2. 
               
            
           
           
               
               
               
            
               
                   
                 Female 
                 Male 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Risk score 
                 OUD No 
                 OUD Yes 
                 Total 
                 OUD No 
                 OUD Yes 
                 Total 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 3 
                 0 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                 4 
                 6 
                 2 
                 8 
                 0 
                 0 
                 0 
               
               
                 5 
                 9 
                 0 
                 9 
                 0 
                 0 
                 0 
               
               
                 6 
                 12 
                 6 
                 18 
                 2 
                 0 
                 2 
               
               
                 7 
                 30 
                 11 
                 41 
                 5 
                 1 
                 6 
               
               
                 8 
                 28 
                 14 
                 42 
                 6 
                 2 
                 8 
               
               
                 9 
                 15 
                 26 
                 41 
                 3 
                 5 
                 8 
               
               
                 10 
                 13 
                 11 
                 24 
                 11 
                 7 
                 18 
               
               
                 11 
                 1 
                 13 
                 14 
                 12 
                 14 
                 26 
               
               
                 12 
                 4 
                 7 
                 11 
                 9 
                 16 
                 25 
               
               
                 13 
                 1 
                 1 
                 2 
                 17 
                 21 
                 38 
               
               
                 14 
                 0 
                 0 
                 0 
                 6 
                 22 
                 28 
               
               
                 15 
                 0 
                 1 
                 1 
                 3 
                 14 
                 17 
               
               
                 16 
                 0 
                 0 
                 0 
                 2 
                 4 
                 6 
               
               
                 17 
                 0 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
            
           
         
       
     
     Model 3: Non-stratified, count SNPs with appropriate number of risk allele copies. Model 3 calculates the risk score in the same way as Model 1, but it does not stratify by sex. Both male and female subjects can accordingly have a risk score ranging from 0 to 19 regardless of their sex/gender. Table 6 provides the distribution of risk scores by OUD in SNP Model 3. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Risk score distribution by OUD in Model 3. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Risk score 
                 OUD No 
                 OUD Yes 
                 Total 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 3 
                 1 
                 0 
                 1 
               
               
                   
                 4 
                 1 
                 1 
                 2 
               
               
                   
                 5 
                 4 
                 1 
                 5 
               
               
                   
                 6 
                 18 
                 6 
                 24 
               
               
                   
                 7 
                 28 
                 10 
                 38 
               
               
                   
                 8 
                 30 
                 28 
                 58 
               
               
                   
                 9 
                 35 
                 33 
                 68 
               
               
                   
                 10 
                 34 
                 33 
                 67 
               
               
                   
                 11 
                 23 
                 30 
                 53 
               
               
                   
                 12 
                 12 
                 26 
                 38 
               
               
                   
                 13 
                 8 
                 22 
                 30 
               
               
                   
                 14 
                 1 
                 6 
                 7 
               
               
                   
                 15 
                 0 
                 3 
                 3 
               
               
                   
                 16 
                 0 
                 1 
                 1 
               
               
                   
                 Total 
                 195 
                 200 
                 395 
               
               
                   
                   
               
            
           
         
       
     
     In some embodiments, determining the risk score based upon summing the plurality of counts could include the SNP Model 1: Sex-stratified, count SNPs with appropriate number of risk allele copies approach (sex-stratified single count SNP model). In other embodiments, determining the risk score based upon summing the plurality of counts could include the SNP Model 2: Sex-stratified, count risk alleles, maximum 2 per SNP) approach (sex-stratified double count SNP model). In still other embodiments, determining the risk score based upon summing the plurality of counts could include the SNP Model 3: Non-stratified, count SNPs with appropriate number of risk allele copies approach (non-sex-stratified single count SNP model). 
     Step 3: Model Validation. 
     A receiver operating characteristic (ROC) curve is a performance measurement for classification at multiple threshold levels. The area under the ROC curve (AUROC) is particularly useful to measure the discrimination (or accuracy), which is the ability of the risk score model to correctly classify those with and without OUD. The AUROC takes values from 0 to 1, where a value of 0 indicates a perfectly inaccurate test and a value of 1 reflects a perfectly accurate test. In general, an AUROC of 0.5 indicates no discrimination, 0.7-0.8 is considered acceptable, 0.8 to 0.9 is considered excellent, and more than 0.9 is considered outstanding. Table 7 lists the AUROC results of the three models (SNP Model 1, SNP Model 2, and SNP Model 3) discussed in Step 2 above. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Area under the ROC curve 
               
            
           
           
               
               
            
               
                   
                 AUROC 
               
            
           
           
               
               
               
               
            
               
                   
                 Female 
                 Male 
                 All 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Model 1 
                 0.9003 
                 0.8831 
                 n/a 
               
               
                   
                 Model 2 
                 0.8885 
                 0.8790 
                 n/a 
               
               
                   
                 Model 3 
                 n/a 
                 n/a 
                 0.8735 
               
               
                   
                   
               
            
           
         
       
     
     The results provided in Table 7 suggest that Model 1 demonstrated excellent accuracy for both female and male subjects.  FIG. 1  and  FIG. 2  plot the ROC curves produced using Model 1. In some embodiments, the AUROC value may range from about 0.6 to about 1.0, from about 0.7 to about 1.0, from about 0.8 to about 1.0, from about 0.9 to about 1.0, from about 0.6 to about 0.7, from about 0.6 to about 0.8, from about 0.6 to about 0.9, from about 0.7 to about 0.8, from about 0.7 to about 0.9, from about 0.7 to about 1.0, from about 0.8 to about 0.9, from about 0.8 to about 1.0, or from about 0.9 to about 1.0. These provided AUROC values may be calculated or determined using Model 1, Model 2, Model 3, or any combinations thereof. 
     Step 4: Cut-Off Analysis 
     Based on the AUROC, SNP Model 1 was identified as being very accurate. Accordingly, the optimal cut-off (threshold) point of the risk score in Model 1 was then tested. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for all possible threshold levels and shown in Table 8 (female) and Table 9 (male). It was estimated that the threshold of risk score 5 for female and 6 for male would maximize the sum of sensitivity and specificity. The sensitivity (“sen”), specificity (“spec”), positive predictive value and negative predictive value are shown in Tables 8 and 9. However, it should be noted that the trade-off between sensitivity and specificity should be considered for each clinical condition. It is possible that choosing a threshold that maximizes the sensitivity while losing some specificity may be more beneficial in some cases (i.e., cancer). 
     The levels of risk with respect to a subject having a genomic susceptibility to opioid use disorder were determined and assigned using the following rules: (1) the level of risk is “low” if the negative predictive value (NPV) is greater than 80%; (2) the level of risk is “moderate” if the NPV is greater than 65% and less than 80%; (3) the level of risk is “high” if the positive predictive value (PPV) is greater than 65%; and (4) the level of risk is “very high” if the PPV is greater than 80%. 
     The risk scoring system using Model 1 to evaluate the 10 SNPs provided in Table 2 for females includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 8, in some embodiments, a female having a risk score less than 3 corresponds to a low chance of OUD; a risk score greater than or equal to 3 and less than 5 corresponds to a moderate chance of OUD; a risk score greater than or equal to 5 and less than or equal to 7 corresponds to a high chance of OUD; and a risk score greater than or equal to 7 corresponds to a very high chance of OUD. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Test Validation Estimates in Model 1 Female. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                 Sen + 
                 Level of 
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Spec 
                 Risk 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 2 
                 99% 
                  8% 
                 46% 
                 91% 
                 107% 
                 low 
               
               
                 3 
                 89% 
                 30% 
                 50% 
                 78% 
                 119% 
                 moderate 
               
               
                 4 
                 73% 
                 61% 
                 60% 
                 74% 
                 134% 
                 moderate 
               
               
                 5 
                 51% 
                 85% 
                 72% 
                 69% 
                 135% 
                 high 
               
               
                 6 
                 25% 
                 94% 
                 77% 
                 62% 
                 119% 
                 high 
               
               
                 7 
                  9% 
                 99% 
                 89% 
                 58% 
                 108% 
                 very high 
               
               
                   
               
            
           
         
       
     
     The risk scoring system using Model 1 to evaluate the 9 SNPs provided in Table 3 for males includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 9, in some embodiments, a male having a risk score less than 4 corresponds to a low chance of OUD; a risk score greater than or equal to 4 and less than 6 corresponds to a moderate chance of OUD; a risk score greater than or equal to 6 and less than or equal to 8 corresponds to a high chance of OUD; and a risk score greater than or equal to 8 corresponds to a very high chance of OUD. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Test Validation Estimates in Model 1 Male. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                 Sen + 
                 Level of 
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 spec 
                 Risk 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 2 
                 100%  
                  1% 
                 59% 
                 100%  
                 101% 
                 low 
               
               
                 3 
                 99% 
                  9% 
                 61% 
                 88% 
                 108% 
                 low 
               
               
                 4 
                 97% 
                 13% 
                 61% 
                 77% 
                 110% 
                 moderate 
               
               
                 5 
                 88% 
                 21% 
                 61% 
                 55% 
                 109% 
                 moderate 
               
               
                 6 
                 78% 
                 50% 
                 69% 
                 61% 
                 128% 
                 high 
               
               
                 7 
                 56% 
                 72% 
                 74% 
                 54% 
                 128% 
                 high 
               
               
                 8 
                 35% 
                 89% 
                 82% 
                 49% 
                 124% 
                 very high 
               
               
                   
               
            
           
         
       
     
     Generally, as thresholds rise, specificity and PPV also rise, but sensitivity falls. In some embodiments, higher sensitivity can be realized by lowering the threshold, albeit at the cost of lower specificity and PPV. Conversely, if higher PPV is required, it can often be realized by raising the threshold, albeit at the cost of lower sensitivity. 
     The levels of risk with respect to a subject having a genomic susceptibility to opioid use disorder were determined and assigned using the following rules: (1) the level of risk is “low” if the negative predictive value (NPV) is greater than 80%; (2) the level of risk is “moderate” if the NPV is greater than 65% and less than 80%; (3) the level of risk is “high” if the positive predictive value (PPV) is greater than 65%; and (4) the level of risk is “very high” if the PPV is greater than 80%. 
     The risk scoring system using SNP Model 2 to evaluate the 10 SNPs provided in Table 2 for females includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 10, in some embodiments, a female having a risk score less than 7 corresponds to a low chance of OUD; a risk score greater than or equal to 7 and less than 10 corresponds to a moderate chance of OUD; a risk score greater than or equal to 11 and less than 14 corresponds to a high chance of OUD; and a risk score greater than or equal to 14 corresponds to a very high chance of OUD. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Test Validation Estimates in Model 2 Female 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 6 
                 97% 
                 13% 
                 46% 
                 83% 
                 110% 
               
               
                 7 
                 90% 
                 23% 
                 48% 
                 75% 
                 113% 
               
               
                 8 
                 78% 
                 48% 
                 54% 
                 74% 
                 126% 
               
               
                 9 
                 63% 
                 71% 
                 63% 
                 71% 
                 134% 
               
               
                 10 
                 35% 
                 84% 
                 63% 
                 63% 
                 119% 
               
               
                 11 
                 24% 
                 95% 
                 79% 
                 61% 
                 119% 
               
               
                 12 
                 10% 
                 96% 
                 64% 
                 58% 
                 106% 
               
               
                 13 
                  2% 
                 99% 
                 67% 
                 56% 
                 101% 
               
               
                 14 
                  1% 
                 100%  
                 100%  
                 56% 
                 101% 
               
               
                 15 
                  1% 
                 100%  
                 100%  
                 56% 
                 101% 
               
               
                   
               
            
           
         
       
     
     The risk scoring system using Model 2 to evaluate the 9 SNPs provided in Table 3 for males includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 11, in some embodiments, a male having a risk score less than 10 corresponds to a low chance of OUD; a risk score equal to 10 corresponds to a moderate chance of OUD; a risk score greater than or equal to 11 corresponds to a high chance of OUD. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Test Validation estimates in Model 2 Male 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 7 
                 100%  
                  3% 
                 59% 
                 100%  
                 103% 
               
               
                 8 
                 99% 
                  9% 
                 61% 
                 88% 
                 108% 
               
               
                 9 
                 97% 
                 17% 
                 62% 
                 81% 
                 114% 
               
               
                 10 
                 93% 
                 21% 
                 62% 
                 67% 
                 114% 
               
               
                 11 
                 86% 
                 36% 
                 65% 
                 64% 
                 122% 
               
               
                 12 
                 73% 
                 51% 
                 68% 
                 57% 
                 124% 
               
               
                 13 
                 58% 
                 63% 
                 69% 
                 52% 
                 121% 
               
               
                 14 
                 38% 
                 86% 
                 79% 
                 50% 
                 124% 
               
               
                 15 
                 18% 
                 93% 
                 79% 
                 45% 
                 111% 
               
               
                 16 
                  5% 
                 97% 
                 71% 
                 42% 
                 102% 
               
               
                   
               
            
           
         
       
     
     The risk scoring system using Model 3 to evaluate the 19 SNPs provided in Tables 2 and 3 for both females and males includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 12, in some embodiments, a subject having a risk score less than 5 corresponds to a low chance of OUD; a risk score greater than or equal to 5 or less than 11 corresponds to a moderate chance of OUD; a risk score greater than or equal to 11 and less than 14 corresponds to a high chance of OUD; and a risk score greater than or equal to 14 corresponds to a very high chance of OUD. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Test Validation Estimates in Model 3 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 4 
                 100%  
                  1% 
                 51% 
                 100%  
                 101% 
               
               
                 5 
                 100%  
                  1% 
                 51% 
                 67% 
                 101% 
               
               
                 6 
                 99% 
                  3% 
                 51% 
                 75% 
                 102% 
               
               
                 7 
                 96% 
                 12% 
                 53% 
                 75% 
                 108% 
               
               
                 8 
                 91% 
                 27% 
                 56% 
                 74% 
                 118% 
               
               
                 9 
                 77% 
                 42% 
                 58% 
                 64% 
                 119% 
               
               
                 10 
                 61% 
                 60% 
                 61% 
                 60% 
                 121% 
               
               
                 11 
                 44% 
                 77% 
                 67% 
                 57% 
                 121% 
               
               
                 12 
                 29% 
                 89% 
                 73% 
                 55% 
                 118% 
               
               
                 13 
                 16% 
                 95% 
                 78% 
                 53% 
                 111% 
               
               
                 14 
                  5% 
                 99% 
                 91% 
                 51% 
                 104% 
               
               
                 15 
                  2% 
                 100%  
                 100%  
                 50% 
                 102% 
               
               
                   
               
            
           
         
       
     
     Relapse Risk Scoring 
     In some embodiments, a method for assessing whether a subject is at risk of opioid relapse is provided. The method comprises: (1) obtaining a biological sample from a subject; (2) performing an allelic analysis on the biological sample to determine the presence of a plurality of pre-determined alleles, wherein the plurality of pre-determined alleles comprise two or more genomic targets selected from Table 1; (3) assigning a count for each of the alleles in the plurality of pre-determined alleles that was present in the biological sample; (4) determining a risk score based upon a total count using a SNP Model, wherein the risk score identifies a severity of the genetic predisposition to opioid addiction; and (5) administering a medical assisted treatment procedure based on the risk score identified in the subject. 
     In some embodiments, a method of obtaining and utilizing a relapse risk score for assessing a genetic predisposition to addiction relapse is provided. The method comprises: (1) obtaining a biological sample from a subject; (2) performing an allelic analysis on the biological sample to determine the presence of a plurality of pre-determined alleles by assigning a plurality of counts, wherein the plurality of pre-determined alleles comprise one or more genomic targets selected from Table 1; (3) determining a risk score based upon summing the plurality of counts; (4) comparing the risk score with one or more predetermined reference values, wherein the subject is determined to have a risk level of opioid addiction if the risk score is greater than a threshold value using a SNP model; and (5) administering a medical assisted treatment procedure based on the risk score identified in the subject. 
     Upon determination of an opioid relapse risk score using a plurality of risk alleles selected from Table 1, a medical assisted treatment procedure or patient therapy may then be provided to the patient. Patients determined to be at higher risk of relapse could receive reduced quantities of opioids dispensed and/or receive increased monitoring/more frequent visits. Conversely, patients determined to be at a lower risk of relapse may require less frequent monitoring and may be appropriate for receiving larger quantities of opioids between prescription fills. Additionally, patients determined to be at a higher risk of relapse may have justification for longer inpatient rehabilitation stays and/or longer intensive outpatient rehabilitation support. Conversely, patients determined to be at a lower risk of relapse may justify an earlier transition from inpatient rehabilitation to intensive outpatient rehabilitation. There may be additional benefit for patients to understand their own risks so as to have a better appreciation for the genetic basis of disease and empowerment over their own treatment decisions. 
     In developing the scoring technique to determine OUD relapse risk, some SNPs need a single copy of the risk allele to elevate the risk of OUD relapse, while other SNPs need two copies of the risk allele to elevate the risk of OUD relapse. The OUD relapse risk score modeling process, as used herein, includes the following steps: Step 1) identify risk alleles and the number needed to express the risk; Step 2) develop one or more risk score models to predict OUD relapse; Step 3) Choose an accurate model based on area under the receiver operating characteristic curve (AUROC); and Step 4) determine clinically reasonable threshold points. 
     In developing the scoring technique to determine opioid relapse risk, the following factors may be considered including that a mutation type allele or wild type allele could be a risk allele. 
     Step 1: Identifying Risk SNP and Allele 
     A set of logistic regression was conducted to identify SNPs that are significantly associated with OUD relapse among persons receiving a buprenorphine-naloxone combination as a medication-assisted treatment (MAT). Each SNP was coded to have three levels: a) having two wild type copies, b) having one wild type copy and one mutation copy, and c) two mutation copies. Two odds ratios (ORs) were calculated for each SNP. First, the odds of having OUD between those with two wild type copies and those with one or more mutation copies were compared. Second, the odds of having OUD between those with two mutation copies and those with one or more wild type copies were compared. An OR was determined as significant if the p-value was 0.05 or less. Because the strength of association between certain SNPs and relapse could be different between male and female, the analysis was stratified by sex. As a result, 9 SNPs/phenotype for female and 6 SNPs/phenotype for male were identified as being significantly associated with relapse. Two SNPs were identified as significantly associated with relapse in the group as a whole, however those were not significant in a stratified group (potentially due to smaller sample size). A listing of those SNPs and their corresponding risk alleles are shown in Tables 13-15. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 SNPs Significantly Associated with Opioid Relapse in Females. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Risk 
                   
                   
                   
               
               
                   
                 Gene 
                 Risk 
                 Geno- 
                   
                   
                   
               
               
                 Assay name 
                 Symbol 
                 Allele 
                 type 
                 NCBI SNP 
                 OR 
                 P-value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 CNIH3 c198 + 21550C &gt; T 
                 CNIH3 
                 C 
                 C/C 
                 rs1369846 
                 3.85 
                 0.036 
               
               
                 CNIH3 c198 + 9283A &gt; G 
                 CNIH3 
                 A 
                 A/A 
                 rs1436171 
                 3.7 
                 0.033 
               
               
                 GRIN3A c2766 + 7656A &gt; T 
                 GRIN3A 
                 A 
                 A/A 
                 rs17189632 
                 4.17 
                 0.037 
               
               
                 HTR3B c213 + 804T &gt; C 
                 HTR3B 
                 C 
                 T/C, 
                 rs11606194 
                 6.45 
                 0.011 
               
               
                   
                   
                   
                 C/T, 
                   
                   
                   
               
               
                   
                   
                   
                 or C/C 
                   
                   
                   
               
               
                 OPRD1 c921C &gt; T 
                 OPRD1 
                 C 
                 C/C 
                 rs2234918 
                 3.7 
                 0.033 
               
               
                 WLS c107-301T &gt; G 
                 WLS 
                 G 
                 G/G 
                 rs1036066 
                 6.67 
                 0.018 
               
               
                 intergenic g.193494720G &gt; A 
                 intergenic 
                 G 
                 G/A, 
                 rs965972 
                 7.69 
                 0.029 
               
               
                   
                   
                   
                 A/G, 
                   
                   
                   
               
               
                   
                   
                   
                 or G/G 
                   
                   
                   
               
               
                 MTHFR 677C &gt; T 
                 MTHFR 
                 C/C 
                 C/C 
                 rs1801133 
                 6.25 
                 0.009 
               
               
                   
                   
                 (G/G) 
                 (G/G) 
                   
                   
                   
               
               
                 CYP2C9 non EM (IM or 
                   
                   
                   
                   
                 3.36 
                 0.043 
               
               
                 PM) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 SNPs Significantly Associated with Opioid Relapse in Males. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Risk 
                   
                   
                   
               
               
                   
                 Gene 
                 Risk 
                 Geno- 
                   
                   
                   
               
               
                 Assay name 
                 Symbol 
                 Allele 
                 type 
                 NCBI SNP 
                 OR 
                 P-value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 DRD3 c-155-2597T &gt; C 
                 DRD3 
                 T 
                 T/T 
                 rs9825563 
                 5.13 
                 0.019 
               
               
                 GAL c-1998C &gt; T 
                 GAL 
                 T 
                 T/T 
                 rs948854 
                 4.01 
                 0.046 
               
               
                 NR4A2 g.156377320C &gt; G 
                 NR4A2 
                 C 
                 C/G, 
                 rs1405735 
                 3.57 
                 0.033 
               
               
                   
                   
                   
                 G/C, or 
                   
                   
                   
               
               
                   
                   
                   
                 C/C 
                   
                   
                   
               
               
                 OPRM c643 + 31G &gt; A 
                 OPRM 
                 A 
                 G/A, 
                 rs9479757 
                 3.82 
                 0.034 
               
               
                   
                   
                   
                 A/G, or 
                   
                   
                   
               
               
                   
                   
                   
                 A/A 
                   
                   
                   
               
               
                 CYP3A4*22 intron6 
                 CYP3A4 
                 T (A) 
                 C/T 
                 rs35599367 
                 13 
                 0.006 
               
               
                 15389C &gt; T 
                   
                   
                 (G/A), 
                   
                   
                   
               
               
                   
                   
                   
                 T/C 
                   
                   
                   
               
               
                   
                   
                   
                 (A/G), 
                   
                   
                   
               
               
                   
                   
                   
                 or T/T 
                   
                   
                   
               
               
                   
                   
                   
                 (A/A) 
                   
                   
                   
               
               
                 CYP 3A4 IM 
                   
                   
                   
                   
                 13 
                 0.006 
               
               
                   
               
            
           
         
       
     
     In male subjects, CYP3A4*22 intron6 15389C&gt;T (rs35599367) predicted the CYP3A4 phenotype perfectly. As a result, the estimate has the same odds ratio and p-value. This was not the case in female subjects. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 SNPs that are significantly associated with 
               
               
                 relapse in a male and female combined group. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Risk 
                   
                   
                   
               
               
                   
                 Gene 
                 Risk 
                 Geno- 
                   
                   
                   
               
               
                 Assay name 
                 Symbol 
                 Allele 
                 type 
                 NCBI SNP 
                 OR 
                 P-value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 DRD3 c25G &gt; A 
                 DRD3 
                 A 
                 A/A 
                 rs6280 
                 3 
                 0.009 
               
               
                 SORCS3 c628-28349A &gt; G 
                 SORCS3 
                 G 
                 A/G, 
                 rs728453 
                 3.06 
                 0.018 
               
               
                   
                   
                   
                 G/A, 
                   
                   
                   
               
               
                   
                   
                   
                 or G/G 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, the SNP Model may include determining a weighted algorithm based on the ORs of the 9 SNPs/phenotype for female, 6 SNPs/phenotype for male, 2 SNPs for both sexes with p-values of 0.05 or less, as provided in Tables 13-15 above. The weighted algorithm may be further based on the genetic codes as well as clinical (phenotype) data utilizing a logistic regression separately between male and female SNPs. 
     Step 2: Relapse Risk Score Modeling 
     Model 1: Sex-stratified, count SNPs with appropriate number of risk allele copies. The OUD relapse risk score was calculated as the sum of SNPs that had the risk alleles as identified above (Tables 13, 14, and 15). For example, GAL (rs948854) was not counted towards the risk score if a subject has C/T, because two copies of T are required in order it to be counted. Similarly, OPRM (rs9479757) was counted only once if a subject had at least one copy of A, regardless of the number of copies. For CYP2C9 phenotype, if a subject was not an EM, 1 was added towards the risk score. Also, two SNPs that are significantly associated with relapse in a male and female combined group (Table 15) were used in calculating risk scores for each of male and female. Female subjects can have a risk score ranging from 0 to 11 and male subjects can have a risk score ranging from 0 to 7. Table 16 shows the distribution of risk scores by relapse in male and female. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Risk score distribution by relapse in Model 1. 
               
            
           
           
               
               
               
            
               
                   
                 Female 
                 Male 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Risk 
                 Relapse 
                 Relapse 
                   
                 Relapse 
                 Relapse 
                   
               
               
                 score 
                 No 
                 Yes 
                 Total 
                 No 
                 Yes 
                 Total 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 0 
                 4 
                 0 
                 4 
                 7 
                 0 
                 7 
               
               
                 1 
                 10 
                 0 
                 10 
                 20 
                 0 
                 20 
               
               
                 2 
                 15 
                 0 
                 15 
                 23 
                 2 
                 25 
               
               
                 3 
                 12 
                 2 
                 14 
                 14 
                 3 
                 17 
               
               
                 4 
                 6 
                 6 
                 12 
                 3 
                 7 
                 10 
               
               
                 5 
                 0 
                 3 
                 3 
                 0 
                 1 
                 1 
               
               
                 6 
                 0 
                 2 
                 2 
                 0 
                 1 
                 1 
               
               
                 7 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 8 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 9 
                 0 
                 0 
                 0 
                   
                   
                   
               
               
                 10 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 11 
                 0 
                 0 
                 0 
                   
                   
                   
               
               
                 Total 
                 47 
                 16 
                 63 
                 67 
                 14 
                 81 
               
               
                   
               
            
           
         
       
     
     Model 2: Sex-stratified, count risk alleles, maximum 2 per SNP. The OUD relapse risk score was calculated as the sum of risk alleles. For example, if a subject had “G/A” for SORCS3 (rs728453), 1 was added towards the risk score. On the other hand, if a subject had “G/G” for SORCS3, 2 was added towards the risk score because two risk alleles were present. For CYP2C9 phenotype, if a subject was not an EM, 1 was added towards the risk score. Female subjects can have a risk score ranging from 0 to 21 and male subjects can have a risk score ranging from 0 to 13. The distribution of risk scores by relapse shown in Table 17. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Risk score distribution by relapse in Model 2. 
               
            
           
           
               
               
               
            
               
                   
                 Female 
                 Male 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Risk 
                 Relapse 
                 Relapse 
                   
                 Relapse 
                 Relapse 
                   
               
               
                 score 
                 No 
                 Yes 
                 Total 
                 No 
                 Yes 
                 Total 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 1 
                 0 
                 0 
                 0 
                 1 
                 0 
                 1 
               
               
                 2 
                 1 
                 0 
                 1 
                 2 
                 0 
                 2 
               
               
                 3 
                 2 
                 0 
                 2 
                 10 
                 0 
                 10 
               
               
                 4 
                 1 
                 0 
                 1 
                 16 
                 0 
                 16 
               
               
                 5 
                 3 
                 1 
                 4 
                 19 
                 3 
                 22 
               
               
                 6 
                 9 
                 1 
                 10 
                 16 
                 2 
                 18 
               
               
                 7 
                 7 
                 1 
                 8 
                 2 
                 7 
                 9 
               
               
                 8 
                 8 
                 1 
                 9 
                 1 
                 1 
                 2 
               
               
                 9 
                 9 
                 1 
                 10 
                 0 
                 1 
                 1 
               
               
                 10 
                 4 
                 2 
                 6 
                   
                   
                   
               
               
                 11 
                 3 
                 4 
                 7 
                   
                   
                   
               
               
                 12 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 13 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 14 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 15 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 16 
                 0 
                 0 
                 0 
                   
                   
                   
               
               
                 17 
                 0 
                 1 
                 1 
                   
                   
                   
               
               
                 Total 
                 47 
                 16 
                 63 
                 67 
                 14 
                 81 
               
               
                   
               
            
           
         
       
     
     Model 3: Non-stratified, count SNPs with appropriate number of risk allele copies. Model 3 calculates the risk score in the same way as Model 1, but it does not stratify by sex. Subjects can have a risk score ranging from 0 to 16 regardless of sex. Table 18 shows the distribution of risk scores by relapse in Model 3. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Risk score distribution by relapse in Model 3. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Risk score 
                 Relapse No 
                 Relapse Yes 
                 Total 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 0 
                 1 
                 0 
                 1 
               
               
                   
                 1 
                 9 
                 0 
                 9 
               
               
                   
                 2 
                 16 
                 0 
                 16 
               
               
                   
                 3 
                 22 
                 1 
                 23 
               
               
                   
                 4 
                 34 
                 1 
                 35 
               
               
                   
                 5 
                 14 
                 14 
                 28 
               
               
                   
                 6 
                 11 
                 3 
                 14 
               
               
                   
                 7 
                 7 
                 6 
                 13 
               
               
                   
                 8 
                 0 
                 1 
                 1 
               
               
                   
                 9 
                 0 
                 2 
                 2 
               
               
                   
                 10 
                 0 
                 0 
                 0 
               
               
                   
                 11 
                 0 
                 1 
                 1 
               
               
                   
                 12 
                 0 
                 1 
                 1 
               
               
                   
                 Total 
                 114 
                 30 
                 144 
               
               
                   
                   
               
            
           
         
       
     
     In some embodiments, determining the risk score based upon summing the plurality of counts could include the SNP Model 1: Sex-stratified, count SNPs with appropriate number of risk allele copies approach (sex-stratified single count SNP model). In other embodiments, determining the risk score based upon summing the plurality of counts could include the SNP Model 2: Sex-stratified, count risk alleles, maximum 2 per SNP approach (sex-stratified double count SNP model). In still other embodiments, determining the risk score based upon summing the plurality of counts could include the SNP Model 3: Non-stratified, count SNPs with appropriate number of risk allele copies approach (non-sex-stratified single count SNP model). 
     Step 3: Model Validation. 
     Receiver operating characteristic (ROC) curve is a performance measurement for classification at multiple threshold levels. The area under the ROC curve (AUROC) is particularly useful to measure the discrimination (or accuracy), which is the ability of the risk score model to correctly classify those with and without OUD. The AUROC takes values from 0 to 1, where a value of 0 indicates a perfectly inaccurate test and a value of 1 reflects a perfectly accurate test. In general, an AUROC of 0.5 indicates no discrimination, 0.7-0.8 is considered acceptable, 0.8 to 0.9 is considered excellent, and more than 0.9 is considered outstanding. Table 19 shows the AUROC results of the three models (SNP Model 1, SNP Model 2, and SNP Model 3) developed in Step 2. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Area under the ROC curve 
               
            
           
           
               
               
            
               
                   
                 AUROC 
               
            
           
           
               
               
               
               
            
               
                   
                 Female 
                 Male 
                 All 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Model 1 
                 0.9621 
                 0.8971 
                 n/a 
               
               
                   
                 Model 2 
                 0.8025 
                 0.8737 
                 n/a 
               
               
                   
                 Model 3 
                 n/a 
                 n/a 
                 0.7266 
               
               
                   
                   
               
            
           
         
       
     
     The results provided in Table 19 suggest that Model 1 demonstrated excellent accuracy for both female and male.  FIG. 3  and  FIG. 4  show the ROC curves from Model 1. In some embodiments, the AUROC value may range from about 0.6 to about 1.0, from about 0.7 to about 1.0, from about 0.8 to about 1.0, from about 0.9 to about 1.0, from about 0.6 to about 0.7, from about 0.6 to about 0.8, from about 0.6 to about 0.9, from about 0.7 to about 0.8, from about 0.7 to about 0.9, from about 0.7 to about 1.0, from about 0.8 to about 0.9, from about 0.8 to about 1.0, from about 0.9 to about 1.0. These provided AUROC values may be calculated or determined using Model 1, Model 2, Model 3, or any combinations thereof 
     Step 4: Cut-Off Analysis 
     Based on the AUROC, SNP Model 1 was identified as an accurate means of analysis. Therefore, in the next step, the optimal cut-off (threshold) point of the risk score in Model 1 was tested. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for all possible threshold levels and shown in Table 20 (female) and Table 21 (male). It was estimated that the threshold of risk score 4 for female and male would maximize the sum of sensitivity and specificity. However, it should be noted that the trade-off between sensitivity and specificity should be considered for each clinical condition. It is possible that choosing a threshold that maximizes the sensitivity while losing some specificity may be more beneficial in some cases (i.e., cancer). Generally, as thresholds rise, specificity and PPV also rise, but sensitivity falls. If higher sensitivity is desired, it can often be realized by lowering the threshold, albeit at the cost of lower specificity and PPV. Conversely, if higher PPV is required, it can often be realized by raising the threshold, albeit at the cost of lower sensitivity. Arbitrarily, we used the risk score threshold that generates the maximum sum of sensitivity and specificity as being associated with a moderate risk of relapse (yellow flag). 
     The risk scoring system using Model 1 to evaluate the 9 SNPs provided in Table 13 and 2 SNPs provided in Table 15 for females includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 20, in some embodiments, a female having a risk score less than 4 corresponds to a low chance of relapse; a risk score equal to 4 corresponds to a moderate chance of relapse; and a risk score greater than 4 corresponds to a high chance of relapse. 
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Test validation estimates in Model 1 female. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 2 
                 100%  
                  30% 
                  33% 
                 100%  
                 130% 
               
               
                 3 
                 100%  
                  62% 
                  47% 
                 100%  
                 162% 
               
               
                 4 
                 88% 
                  87% 
                  70% 
                 95% 
                 175% 
               
               
                 5 
                 50% 
                 100% 
                 100% 
                 85% 
                 150% 
               
               
                 6 
                 31% 
                 100% 
                 100% 
                 81% 
                 131% 
               
               
                 7 
                 19% 
                 100% 
                 100% 
                 78% 
                 119% 
               
               
                 8 
                 13% 
                 100% 
                 100% 
                 77% 
                 113% 
               
               
                 9 
                  6% 
                 100% 
                 100% 
                 76% 
                 106% 
               
               
                 10 
                  6% 
                 100% 
                 100% 
                 76% 
                 106% 
               
               
                   
               
            
           
         
       
     
     The risk scoring system using Model 1 to evaluate the 5 SNPs provided in Table 14 and 2 SNPs provided in Table 15 for males includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 21, in some embodiments, a male having a risk score less than 4 corresponds to a low chance of relapse; a risk score equal to 4 corresponds to a moderate chance of relapse; and a risk score greater than 4 corresponds to a high chance of relapse. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Test validation estimates in Model 1 male. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 2 
                 100%  
                 40% 
                 26% 
                 100%  
                 140% 
               
               
                 3 
                 86% 
                 75% 
                 41% 
                 96% 
                 160% 
               
               
                 4 
                 64% 
                 96% 
                 75% 
                 93% 
                 160% 
               
               
                 5 
                 14% 
                 100%  
                 100%  
                 85% 
                 114% 
               
               
                 6 
                  7% 
                 100%  
                 100%  
                 84% 
                 107% 
               
               
                   
               
            
           
         
       
     
     The risk scoring system using Model 2 to evaluate the 9 SNPs provided in Table 13 and 2 SNPs provided in Table 15 for females includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 22, in some embodiments, a female having a risk score less than 10 corresponds to a low chance of relapse; a risk score equal to 10 corresponds to a moderate chance of relapse; and a risk score greater than 10 corresponds to a high chance of relapse. 
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Test validation estimates in Model 2 female. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 4 
                 100%  
                  6% 
                 27% 
                 100%  
                 106% 
               
               
                 5 
                 100%  
                  9% 
                 27% 
                 100%  
                 109% 
               
               
                 6 
                 94% 
                 15% 
                 27% 
                 88% 
                 109% 
               
               
                 7 
                 88% 
                 34% 
                 31% 
                 89% 
                 122% 
               
               
                 8 
                 81% 
                 49% 
                 35% 
                 88% 
                 130% 
               
               
                 9 
                 75% 
                 66% 
                 43% 
                 89% 
                 141% 
               
               
                 10 
                 69% 
                 85% 
                 61% 
                 89% 
                 154% 
               
               
                 11 
                 56% 
                 94% 
                 75% 
                 86% 
                 150% 
               
               
                 12 
                 31% 
                 100%  
                 100%  
                 81% 
                 131% 
               
               
                 13 
                 25% 
                 100%  
                 100%  
                 80% 
                 125% 
               
               
                 14 
                 19% 
                 100%  
                 100%  
                 78% 
                 119% 
               
               
                 15 
                 13% 
                 100%  
                 100%  
                 77% 
                 113% 
               
               
                   
               
            
           
         
       
     
     The risk scoring system using Model 2 to evaluate the 5 SNPs provided in Table 14 and 2 SNPs provided in Table 15 for males includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 23, in some embodiments, a male having a risk score less than 7 corresponds to a low chance of relapse; a risk score equal to 7 corresponds to a moderate chance of relapse; and a risk score greater than 7 corresponds to a high chance of relapse. 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Test validation estimates in Model 2 male. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 4 
                 88% 
                  28% 
                 21% 
                 100%  
                 115% 
               
               
                 5 
                 88% 
                  62% 
                 27% 
                 100%  
                 149% 
               
               
                 6 
                 69% 
                 102% 
                 37% 
                 94% 
                 171% 
               
               
                 7 
                 56% 
                 136% 
                 75% 
                 93% 
                 192% 
               
               
                 8 
                 13% 
                 140% 
                 67% 
                 85% 
                 153% 
               
               
                 9 
                  6% 
                 143% 
                 100%  
                 84% 
                 149% 
               
               
                   
               
            
           
         
       
     
     The risk scoring system using Model 3 to evaluate the 14 SNPs or 16 SNPs provided in Tables 13-15 for both females and males includes different levels of risk based on the subject&#39;s corresponding risk score. Referring to Table 24, in some embodiments, a subject having a risk score less than 5 corresponds to a low chance of relapse; a risk score equal to 5 corresponds to a moderate chance of relapse; and a risk score greater than 5 corresponds to a high chance of relapse. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Test validation estimates in Model 3 
               
            
           
           
               
               
               
               
               
               
            
               
                 Risk score 
                   
                   
                   
                   
                   
               
               
                 threshold 
                 Sensitivity 
                 Specificity 
                 PPV 
                 NPV 
                 Sen + spec 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 2 
                 100%  
                  9% 
                 22% 
                 100%  
                 109% 
               
               
                 3 
                 100%  
                 23% 
                 25% 
                 100%  
                 123% 
               
               
                 4 
                 97% 
                 42% 
                 31% 
                 98% 
                 139% 
               
               
                 5 
                 93% 
                 72% 
                 47% 
                 98% 
                 165% 
               
               
                 6 
                 47% 
                 84% 
                 44% 
                 86% 
                 131% 
               
               
                 7 
                 37% 
                 94% 
                 61% 
                 85% 
                 131% 
               
               
                 8 
                 17% 
                 100%  
                 100%  
                 82% 
                 117% 
               
               
                 9 
                 13% 
                 100%  
                 100%  
                 81% 
                 113% 
               
               
                 10 
                  7% 
                 100%  
                 100%  
                 80% 
                 107% 
               
               
                   
               
            
           
         
       
     
     Examples 
     TaqMan SNP Genotyping 
     A SNP (single nucleotide polymorphism) is a change in the sequence of a gene at a specific locus. The sequence that matches the “normal” gene sequence is referred to as the wild-type allele, and the sequence that contains the change is referred to as the variant allele. A single gene may contain multiple SNPs that correspond with a functional alteration. 
     TaqMan SNP Genotyping Assays were obtained from Life Technologies. Each SNP assay contained primers and sequence-specific probes for identifying both the wild-type allele and the variant allele for a single SNP locus. The probes for the wild-type and variant alleles were tagged with different fluorophores. For example, an assay for a wild-type allele may contain a FAM probe and the corresponding variant allele assay may contain a VIC probe. Each probe emits a signal that is detectable at a different wavelength. The detector of the instrument measured the amount of each fluorescent signal in each reaction well. Gene sequence determinations were made based on the fluorescent signal as described below. 
     Genomic DNA (gDNA) contains two alleles, one inherited from each parent. Each allele pair is either the same (homozygous) or different (heterozygous). SNP genotyping data was performed by using these assays and analyzed using TaqMan Genotyper software provided amplification for only FAM (homozygous), only VIC (homozygous), or both FAM and VIC (heterozygous). 
     Genomic DNA Isolation 
     Genomic DNA (gDNA) was isolated from the buccal swab samples using a Maxwell 16 LEV Blood DNA kit according to the manufacturer&#39;s suggested protocol (Promega). gDNA quality and concentration were measured using a NanoDrop 2000 spectrophotometer (Thermo Scientific). 
     SNP Genotyping 
     SNPs were identified using Taqman qPCR chemistry, with assays run in an OpenArray format. A reaction mix, containing 50 ng gDNA (diluted with nuclease-free water) and Universal Master Mix II w/UNG were prepared. The reaction mix was then loaded into the OpenArray using an automated AccuFil instrument. The OpenArrays were run in a QuantStudio 12K Flex instrument (Life Technologies) using the following cycling parameters: 2 minutes @ 50° C.; 10 minutes @95° C.; and 50 cycles of 15 seconds at 92° C./90 seconds at 60° C. 
     Control Samples 
     Positive control samples (gDNA samples from individuals with a confirmed genotype) were obtained for the Coriell Control Databank and positive control samples were included on each OpenArray. 
     Data Analysis 
     Genetic test data generated included raw data files from 2 software programs—Genotyper and CopyCaller (Life Technologies). Each patient&#39;s data was analyzed, collated and assembled into a lab report template. 
     For some genes, there were multiple assays per gene. In order to produce a genotype determination, two separate companies were contracted: 1) Translational Software (TS, Seattle, Wash.)—analyzed the raw data files to produce a genotype call based on the individual assay data. and 2) Arivium, Inc. (Grand Rapids, Mich.)—to serve as the hosted LIMS system. Arivium developed a custom LIMS system that operates via a web-based portal to: a) transfer raw data, b) store reports. 
     Referring to Table 25, commonly used gene sequences and their corresponding SNPs for sixty (60) genes used to provide a risk score based upon the summing of counts is provided. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Sequences 
               
            
           
           
               
               
               
               
            
               
                   
                 Gene 
                 Genomic 
                   
               
               
                 Seq No. 
                 Symbol 
                 Location 
                 Sequence 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 ANKK1 
                 chr11: 113399438 
                 TCCCGTCAGGCTGACCCCAACCTGC A   
               
               
                   
                   
                   
                 TGAGGCTGAGGGCAAGACCCCCCTC 
               
               
                   
               
               
                 2 
                 ANKK1 
                 chr11: 113399438 
                 TCCCGTCAGGCTGACCCCAACCTGC G   
               
               
                   
                   
                   
                 TGAGGCTGAGGGCAAGACCCCCCTC 
               
               
                   
               
               
                 3 
                 BDNFOS/ 
                 chr11: 27643996 
                 TACACAGGTGAATGAAAATGTCCAC C   
               
               
                   
                 antiBDNF 
                   
                 GCTCTAGAAGAGTTTATACAAATAA 
               
               
                   
               
               
                 4 
                 BDNFOS/ 
                 chr11: 27643996 
                 TACACAGGTGAATGAAAATGTCCAC T   
               
               
                   
                 antiBDNF 
                   
                 GCTCTAGAAGAGTTTATACAAATAA 
               
               
                   
               
               
                 5 
                 CNIH3 
                 chr1: 224706393 
                 CAGGCAATGACGCACATAGCATCCT C   
               
               
                   
                   
                   
                 GCCTGTTCCGGAGGGTCGCCTTTGA 
               
               
                   
               
               
                 6 
                 CNIH3 
                 chr1: 224706393 
                 CAGGCAATGACGCACATAGCATCCT T   
               
               
                   
                   
                   
                 GCCTGTTCCGGAGGGTCGCCTTTGA 
               
               
                   
               
               
                 7 
                 CNR1 
                 chr6: 88150763 
                 TAGGTTTGTGGATGTGCCAGGACCA C   
               
               
                   
                   
                   
                 GTAAGGAACAGCTCTCTCATATATT 
               
               
                   
               
               
                 8 
                 CNR1 
                 chr6: 88150763 
                 TAGGTTTGTGGATGTGCCAGGACCA T   
               
               
                   
                   
                   
                 GTAAGGAACAGCTCTCTCATATATT 
               
               
                   
               
               
                 9 
                 CREBBP 
                 chr16: 3745362 
                 TCCTTGCAATCAACGAAACTAGGAG A   
               
               
                   
                   
                   
                 CAAAGAAGGCGCACTGTTAAAGCAC 
               
               
                   
               
               
                 10 
                 CREBBP 
                 chr16: 3745362 
                 TCCTTGCAATCAACGAAACTAGGAG G   
               
               
                   
                   
                   
                 CAAAGAAGGCGCACTGTTAAAGCAC 
               
               
                   
               
               
                 11 
                 CSNK1E 
                 chr22: 38287631 
                 ACTAGGCCTCTCACACTGGATTCTG C A 
               
               
                   
                   
                   
                 TTGGGGTGAACCACTTGCTACTCT 
               
               
                   
               
               
                 12 
                 CSNK1E 
                 chr22: 38287631 
                 ACTAGGCCTCTCACACTGGATTCTG G   
               
               
                   
                   
                   
                 ATTGGGGTGAACCACTTGCTACTCT 
               
               
                   
               
               
                 13 
                 DRD2 
                 chr11: 113425897 
                 CCAAAAATGTAGGGTATGGCAGTAA C   
               
               
                   
                   
                   
                 GTTGAGGATAATTAAACTGCAGGGA 
               
               
                   
               
               
                 14 
                 DRD2 
                 chr11: 113425897 
                 CCAAAAATGTAGGGTATGGCAGTAA T   
               
               
                   
                   
                   
                 GTTGAGGATAATTAAACTGCAGGGA 
               
               
                   
               
               
                 15 
                 DRD2 
                 chr11: 113441417 
                 GGTAGCCTATGGACCACATTTAGCT G   
               
               
                   
                   
                   
                 GCATACAGGATTTGTTGGGCTCACA 
               
               
                   
               
               
                 16 
                 DRD2 
                 chr11: 113441417 
                 GGTAGCCTATGGACCACATTTAGCT T   
               
               
                   
                   
                   
                 GCATACAGGATTTGTTGGGCTCACA 
               
               
                   
               
               
                 17 
                 DRD2 
                 chr11: 113426463 
                 AATTAAACTTATCAGCATTCCAAGG C   
               
               
                   
                   
                   
                 GTTTCATACAAAGCACATGACTTCC 
               
               
                   
               
               
                 18 
                 DRD2 
                 chr11: 113426463 
                 AATTAAACTTATCAGCATTCCAAGG T   
               
               
                   
                   
                   
                 GTTTCATACAAAGCACATGACTTCC 
               
               
                   
               
               
                 19 
                 DRD2 
                 chr11: 113414814 
                 AGGAAACAGGCTCATAGAAGGTAAG 
               
               
                   
                   
                   
                   A AACTTGCCTAAGGTCACTCAGCAAA 
               
               
                   
               
               
                 20 
                 DRD2 
                 chr11: 113414814 
                 AGGAAACAGGCTCATAGAAGGTAAG C   
               
               
                   
                   
                   
                 AACTTGCCTAAGGTCACTCAGCAAA 
               
               
                   
               
               
                 21 
                 DRD2 
                 chr11: 113412966 
                 CCCATCTCACTGGCCCCTCCCTTTC A C 
               
               
                   
                   
                   
                 CCTCTGAAGACTCCTGCAAACACC 
               
               
                   
               
               
                 22 
                 DRD2 
                 chr11: 113412966 
                 CCCATCTCACTGGCCCCTCCCTTTC C C 
               
               
                   
                   
                   
                 CCTCTGAAGACTCCTGCAAACACC 
               
               
                   
               
               
                 23 
                 DRD2/ 
                 chr11: 113425564 
                 GAACCACATGATCAGATTCGCCTTT C   
               
               
                   
                 Taq1B 
                   
                 GAATAGGTGATTCTGACAGCACTGT 
               
               
                   
               
               
                 24 
                 DRD2/ 
                 chr11: 113425564 
                 GAACCACATGATCAGATTCGCCTTT T G 
               
               
                   
                 Taq1B 
                   
                 AATAGGTGATTCTGACAGCACTGT 
               
               
                   
               
               
                 25 
                 DRD3 
                 chr3: 114162776 
                 ATAGGGAAGTGTTAGGTGAGGAGGG A   
               
               
                   
                   
                   
                 TAGTTGTTGGAAAAGGGATGGAAGT 
               
               
                   
               
               
                 26 
                 DRD3 
                 chr3: 114162776 
                 ATAGGGAAGTGTTAGGTGAGGAGGG G   
               
               
                   
                   
                   
                 TAGTTGTTGGAAAAGGGATGGAAGT 
               
               
                   
               
               
                 27 
                 DRD3 
                 chr3: 114140326 
                 AAAAGGCAGGTAATGATATTGTGAC A   
               
               
                   
                   
                   
                 TGGAGAATGTGCACTTAGAAGGGTC 
               
               
                   
               
               
                 28 
                 DRD3 
                 chr3: 114140326 
                 AAAAGGCAGGTAATGATATTGTGAC G   
               
               
                   
                   
                   
                 TGGAGAATGTGCACTTAGAAGGGTC 
               
               
                   
               
               
                 29 
                 DRD4 
                 chr11: 636784 
                 GGGCAGGGGGAGCGGGCGTGGAGGG 
               
               
                   
                   
                   
                   C GCGCACGAGGTCGAGGCGAGTCCGC 
               
               
                   
               
               
                 30 
                 DRD4 
                 chr11: 636784 
                 GGGCAGGGGGAGCGGGCGTGGAGGG 
               
               
                   
                   
                   
                   T GCGCACGAGGTCGAGGCGAGTCCGC 
               
               
                   
               
               
                 31 
                 GABRB3 
                 chr15: 26774621 
                 TCACGTTGGCATGTTTCTGTGCATT A A 
               
               
                   
                   
                   
                 TTTTAAATATACTGCCTTTTTAAA 
               
               
                   
               
               
                 32 
                 GABRB3 
                 chr15: 26774621 
                 TCACGTTGGCATGTTTCTGTGCATT G A 
               
               
                   
                   
                   
                 TTTTAAATATACTGCCTTTTTAAA 
               
               
                   
               
               
                 33 
                 GRIN3B 
                 chr19: 1005231 
                 TTTATGTGGCCCCTGCACTGGTCCA C G 
               
               
                   
                   
                   
                 TGGCTGGGCGTCTTTGCGGCCCTG 
               
               
                   
               
               
                 34 
                 GRIN3B 
                 chr19: 1005231 
                 TTTATGTGGCCCCTGCACTGGTCCA T G 
               
               
                   
                   
                   
                 TGGCTGGGCGTCTTTGCGGCCCTG 
               
               
                   
               
               
                 35 
                 intergenic 
                 chr1: 163535374 
                 TTAGTAGACTTGAATTATAGATGCC A   
               
               
                   
                   
                   
                 CAACTCTCATTCATGTGCATTTCTG 
               
               
                   
               
               
                 36 
                 intergenic 
                 chr1: 163535374 
                 TTAGTAGACTTGAATTATAGATGCC G   
               
               
                   
                   
                   
                 CAACTCTCATTCATGTGCATTTCTG 
               
               
                   
               
               
                 37 
                 OPRD1 
                 chr1: 28855013 
                 AAGGGTACAGCAGGGAACAAAATGG 
               
               
                   
                   
                   
                   A CGAAGTCTTCTGGCTTCAGGGAACT 
               
               
                   
               
               
                 38 
                 OPRD1 
                 chr1: 28855013 
                 AAGGGTACAGCAGGGAACAAAATGG 
               
               
                   
                   
                   
                   G CGAAGTCTTCTGGCTTCAGGGAACT 
               
               
                   
               
               
                 39 
                 OPRD1 
                 chr1: 28863085 
                 CGCTGCACCTGTGCATCGCGCTGGG C   
               
               
                   
                   
                   
                 TACGCCAATAGCAGCCTCAACCCCG 
               
               
                   
               
               
                 40 
                 OPRD1 
                 chr1: 28863085 
                 CGCTGCACCTGTGCATCGCGCTGGG T T 
               
               
                   
                   
                   
                 ACGCCAATAGCAGCCTCAACCCCG 
               
               
                   
               
               
                 41 
                 OPRM1 
                 chr6: 154040884 
                 TGGTGTTGATGTGTATATTCAAATA C T 
               
               
                   
                   
                   
                 ACATGTGAATGTGAAATGCCATAT 
               
               
                   
               
               
                 42 
                 OPRM1 
                 chr6: 154040884 
                 TGGTGTTGATGTGTATATTCAAATA T T 
               
               
                   
                   
                   
                 ACATGTGAATGTGAAATGCCATAT 
               
               
                   
               
               
                 43 
                 PENK 
                 chr8: 56447926 
                 TGTATCCAATCCACCTATGCATCTA C G 
               
               
                   
                   
                   
                 TCTCCTAGACCTAGGGGGAAACCA 
               
               
                   
               
               
                 44 
                 PENK 
                 chr8: 56447926 
                 TGTATCCAATCCACCTATGCATCTA T G 
               
               
                   
                   
                   
                 TCTCCTAGACCTAGGGGGAAACCA 
               
               
                   
               
               
                 45 
                 SLC6A3 
                 chr5: 1446274 
                 CAGCGCGCGGAGGAATGGAGCCCCC A   
               
               
                   
                   
                   
                 GGCCGCCAAGGCCCAGGATGTCCAG 
               
               
                   
               
               
                 46 
                 SLC6A3 
                 chr5: 1446274 
                 CAGCGCGCGGAGGAATGGAGCCCCC G   
               
               
                   
                   
                   
                 GGCCGCCAAGGCCCAGGATGTCCAG 
               
               
                   
               
               
                 47 
                 TACR1 
                 chr2: 75198602 
                 TACTGGCGAAGACAGCGGCGATGGG A   
               
               
                   
                   
                   
                 AAGAAGTTGTGGAACTTGCAGTAGA 
               
               
                   
               
               
                 48 
                 TACR1 
                 chr2: 75198602 
                 TACTGGCGAAGACAGCGGCGATGGG G   
               
               
                   
                   
                   
                 AAGAAGTTGTGGAACTTGCAGTAGA 
               
               
                   
               
               
                 49 
                 TACR1 
                 chr2: 75135918 
                 ACCTCCCCTATATTCTCCCCTCTCC A T 
               
               
                   
                   
                   
                 TTCGCATTCTGTTTCACCATCGTT 
               
               
                   
               
               
                 50 
                 TACR1 
                 chr2: 75135918 
                 ACCTCCCCTATATTCTCCCCTCTCC C T 
               
               
                   
                   
                   
                 TTCGCATTCTGTTTCACCATCGTT 
               
               
                   
               
               
                 51 
                 TACR3 
                 chr4: 103643921 
                 GATAACCCATAGAGAACCTTTTTCA A   
               
               
                   
                   
                   
                 ATGATTGCCAAACACTGAAAGGCTT 
               
               
                   
               
               
                 52 
                 TACR3 
                 chr4: 103643921 
                 GATAACCCATAGAGAACCTTTTTCA G   
               
               
                   
                   
                   
                 ATGATTGCCAAACACTGAAAGGCTT 
               
               
                   
               
               
                 53 
                 TACR3 
                 chr4: 103585232 
                 TAGTCAGTGTGGGTCCTGAGGTTGT A   
               
               
                   
                   
                   
                 GCATGTTTAGCAAAGTTACAGAACA 
               
               
                   
               
               
                 54 
                 TACR3 
                 chr4: 103585232 
                 TAGTCAGTGTGGGTCCTGAGGTTGT G   
               
               
                   
                   
                   
                 GCATGTTTAGCAAAGTTACAGAACA 
               
               
                   
               
               
                 55 
                 WLS 
                 chr1: 68194522 
                 CTTCAAAACAATGTCACAAAAAATC A   
               
               
                   
                   
                   
                 ACTGTGCTACAGTTCCCACCTGATT 
               
               
                   
               
               
                 56 
                 WLS 
                 chr1: 68194522 
                 CTTCAAAACAATGTCACAAAAAATC C   
               
               
                   
                   
                   
                 ACTGTGCTACAGTTCCCACCTGATT 
               
               
                   
               
               
                 57 
                 ZNF804A 
                 chr2: 184668853 
                 ATTTATGAATTTAATTCATTAATGT C G 
               
               
                   
                   
                   
                 TAAATAGTATTGCCCGAGAATTGG 
               
               
                   
               
               
                 58 
                 ZNF804A 
                 chr2: 184668853 
                 ATTTATGAATTTAATTCATTAATGT T G 
               
               
                   
                   
                   
                 TAAATAGTATTGCCCGAGAATTGG 
               
               
                   
               
               
                 59 
                 ZNF804A 
                 chr2: 184913701 
                 AGATATCCAAGAAGTTGATTCTGAT A   
               
               
                   
                   
                   
                 GTTTTTGATTCTTTGTTTCAGTGTT 
               
               
                   
               
               
                 60 
                 ZNF804A 
                 chr2: 184913701 
                 AGATATCCAAGAAGTTGATTCTGAT C   
               
               
                   
                   
                   
                 GTTTTTGATTCTTTGTTTCAGTGTT 
               
               
                   
               
            
           
         
       
     
     The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims. It is further to be understood that all values are approximate, and are provided for description.