# Presentation: 437688

## Genetic Factors and the Directionality of Comorbid Disorders

- University of Pittsburgh

- Michael Vanyukov

- Supported by NIDA grants
- R01DA011922, P50DA005605, R01DA019157, K02DA018701

- mmv@pitt.edu

## Getting to the root(s)

- “The active ingredient in Roundup moves through the weed to kill the root.”

## Phenotyping SUD

- Dx of substance dependence:
- 3 out of nine symptoms
-               466 combinations

- Arbitrary phenotypes—ICD-m, DSM-n

- Staging—opportunistic

- Mixed effects: stimulants & depressants

- And a little bit of this'd get you upAnd a little bit of that'd get you down
-                              Mark Knopfler “*Junkie Doll*”

## Liability, the concept

- “...*to express not only the individual **innate tendency** to develop or contract the disease, i.e., his susceptibility in the usual sense, but also the whole combination of **external circumstances** that make him **more or less likely to develop the disease**...” *
-                                                       Falconer (1965)

**Notes:**
Falconer introduced the notion of the liability for traits that were not inherited in a Mendelian fashion but nevertheless showed non-random familial distribution. 

## Liability distribution

**Notes:**
SUD is a complex disorder. This means that  the distribution of SUD liability is continuous. It is not a continuum of use—abuse—addiction, even though in the suprathreshold area it is related to the severity of the disorder. Rather, this trait comprises all the factors which increase or decrease the risk for substance abuse. The distribution is similar to that for height. The difference is that individual height, that is, height phenotype, is directly measured. The whole distribution can be observed. The liability to substance abuse is observed only inasmuch as affected and nonaffected phenotypes are defined. The threshold dividing them is described, in clinical practice, by a variable set of symptoms currently corresponding to the DSM-IV criteria, and, in research, by changes in the brain, physiology, behavior, et cetera. Additional complexity comes from the fact that the liability to SA is a dynamic trait. The liability phenotype undergoes development from the moment of conception on.

## Shared liability variance

- Tsuang et al., *Harvard Rev Psychiatry*, 9: 267-279, 2001

## More sharing

- Kendler et al., Am J Psychiatry 160: 687–695, 2003

- 0.74

- 0.62

- 0.62

- 0.52

- 0.58

- 0.23

**Cannabis**

**Cocaine**

**Halluc**

**Sedat**

**Stimul**

**Opiate**

**A****c**

**S****c****/U****c**

- 0.01/0.09

- 0.00/0.14

- 0.05/0.25

- 0.07/0.34

- 0.06/0.16

- 0.00/0.64

## Psychiatric and drug abuse disorders

**Kendler, K. S. et al. Arch Gen Psychiatry 2003;60:929-937.**

**Psychiatric and drug abuse disorders**

## Common sources of variation

**Pre****-use**
- Temperament
- Personality
- Cognition
- Behavior
- Self-medication

**Post****-use**
- Positive reinforcement
- Negative reinforcement

**Biobehavioral self-regulation**

## The drug-activated mesocorticolimbic dopamine pathway

- Prefrontal
- cortex

- Nucleus
- accumbens

- Substantia
-  nigra

- Hippocampus

- Locus coeruleus

- Cerebellum

- Ventral tegmental area

- Colliculus

- Periaqueductal
-  gray
-  area

- ALCOHOL

- OPIATES

- COCAINE & AMPHETAMINES

- Striatum

**Dopamine pathway**

- Amygdala

**The drug-activated mesocorticolimbic dopamine pathway**

**Notes:**
The commonality between the mechanisms of the various SUD can be explained by the fact that the reward systems for different drugs, to a large degree, share the same structures of the brain. The cocaine and amphetamine reward system includes neurons of the ventral tegmental area, which are connected to the nucleus accumbens and the prefrontal cortex; the opiate reward system also includes these structures. The Arcuate nucleus (not shown), amygdala, locus coeruleus and periaqueductal gray area are also regions affected by opiates. The alcohol reward system also include VTA and the nucleus accumbens and affects the structures that use GABA as a neurotransmitter: the cortex, cerebellum, hippocampus, superior and inferior colliculi, amygdala, and probably substantia nigra. The VTA and the nucleus accumbens are two structures involved in the reward system for all drugs, including tobacco.

## Sources of SUD risk variation

**Sources of SUD risk variation**

**Notes:**
1. The object of genetics is the genes’ contribution to variation in the risk for substance use disorders. This contribution, estimated by heritability, is based upon the existence of genetic polymorphisms—that is, the presence in the population of different versions—alleles—of genes influencing drug-response-related processes. Depending on the variation in function (for instance, a neurotransmitter receptor) related to a polymorphism and the frequency of the alleles, the polymorphism contributes to the populational variation in the risk for SUD.
2.The influence of genetic polymorphisms on the variation in liability to SUD  is mediated by the traits determining behavioral variation, individual differences in drug metabolism and possibly other factors.
3. These relationship are likely moderated by environmental characteristics, in addition to the 
4. independent contribution of the environment to the phenotypic variation. 
5. Individual phenotypes, in  turn, influence the individual's choice of environment.

## Comorbidity models 

- Chance, bias, stratification
- Alternate forms (single liability)
- Multiformity (having one increases probability of another, threshold-dependent)
- Three independent
- Correlated liabilities (threshold-independent)
- correlated
- one causes another
- reciprocal causation

## Subsample of models

- Rhee et al. J Abnorm Psychol, 114:346-362, 2005

## Genetics in SUD risk

**Notes:**
Connected via two related phenomena – their participation in the  determination of liability and related traits, and their contribution to their variation. 
Involvement in determination results from the genes’ encoding the components of neurobiological systems participating in the individual-drug interaction. By itself, it is of little interest to genetics.

## It’s a long way ...

- polymorphisms

- Genetic

**Notes:**
The point is the paths’ values multiplied result in a progressively weak connection between genetic variation and a behavioral trait such and SUD liability.

## Dynamic liability: Tracking etiology and comorbidity of SUD

**Risk**

## Genetics & comorbidity

- Behavior genetics
- genetic and environmental correlations
- developmental tracking
- Molecular genetics
- association/linkage
- mediation by intermediate traits
- “Hybrids”

## Family history

- Faster physiological maturation
- Detachment from parents
- Homophilic peer selection/contagion
- Dysregulation/disinhibition
- Maladjustment
- SU/SUD

## Determination of SUD liability

- LF

***1*

***2*

***3*

- Transmissible causal variables (e.g., genetic polymorphisms, neurochemical processes, transmissible environment)

- nontransmissible environment

- Psychological variables

- LP – parental liability
- LF – son’s liability

**Determination of SUD liability**

**Notes:**
LP and LF are related, ie, liability is transmissible, due to the genetic and environmental mechanisms that influence nervous system functioning determining relevant pre-use behavior (eg, antisociality, sensation seeking),  drug response determining positive and negative drug reinforcement (including relevant drug metabolism), reciprocal phenotype-environment influences, and GxG, GxE, PxE and other interactions. Liability is also contributed by nontransmissible environment (which may also influence psychological variables – not shown for simplicity).

## DBD and the rate of SUD

- ADHD		2.81	1.42-5.55	0.003
- CD		7.17 	2.78-18.52	0.00005
- ODD		2.20 	1.04-4.63	0.038

**DBD and the rate of SUD**

- dysregulation

## Measurement of SUD liability

- LP – parental liability
- LF – son’s liability

**Notes:**
By selecting psychological constructs differentiating the HAR and LAR groups, we ensure that they and their indicator items are related to transmissible liability (shown by broken lines). The constructs are likely to be related to the  variables from the previous figure, but here they play the role of latent effect indicators of liability in the measurement model, whereas  variables were latent causal indicators in the etiological model. A sufficient number of indicator items allowing to cover the full range of liability values should allow measurement of liability with sufficient precision. Nontransmissible environmental variables cannot provide indicators of the index, because they will not distinguish between the groups. Transmissible environmental variables  will be correlated with the psychological variables through various mechanisms, including through influencing them or being influenced by them or both, and thus are redundant for indicating liability. Therefore inclusion of environment in the measurement scheme would not help index derivation, because it would not change the latent variable it measures, but would violate the assumption that the only (or main) source of correlation between the selected constructs is transmissible SUD liability.

## DRD4-ERP-Disinhibition

- Family-based analysis (FBAT)
- Promoter region (-521) SNP
- ERP—ND: p=.02
- SNP—>P300: p=.004
- SNP—>ND: p=.003
- SNP—>ND|P300: p=.85

## Parenting & MAOA

- Vanyukov et al. (in press) Psychiatric Genetics

## MAOA & SUD

- Low activity
- increase in the risk
- limbic volume reductions, hyperresponsive amygdala during emotional arousal, diminished reactivity of regulatory prefrontal regions (Meyer-Lindenberg et al., 2006)

## Drug use severity

- Drug Use Screening Inventory substance use problems scale
- 94 male Caucasian adolescents (12-18 years of age) with a DSM-IV diagnosis of Substance Dependence related to illicit drugs
- Polymorphisms in DRD1-DRD5 genes
- Two-way ANOVA, testing main effects and interactions between D1- and D2-family genes

- Trait
- Sample
- Genes
- Analysis

## Interactions as expected 

## Candidate system genes

*Comorbidity helps:*
- multiple hits
- cross-verify
- identify pathways
- support the gene’s role

## Dynamic 

**c3**

**G****c**

**h3**

**e3**

-  **E****c1**

-  **E****c3**

-  **E****c2**

**c2**

**h2**

**e2**

**c1**

**h1**

**e1**

- T1

- T2

- T3

**Dynamic **

- frozen

- birth

- time

- Note: G×E omitted

## Genetic roots

- ... environmental “Roundup”?