# Presentation: 861831

## Neurophysiological Endophenotypes, CNS Disinhibition and Risk for Alcohol Dependence and Related Disorders

**Prof. Bernice Porjesz**
**Director, Henri Begleiter Neurodynamics Laboratory**
**SUNY Downstate Medical Center, Brooklyn, New York **
**Presenter: ****	****Andrew C. Chen, MD, PhD**
**	****	****Assistant Professor of Psychiatry, SUNY Downstate**
**	****	****Attending Psychiatrist, University Hospital of Brooklyn**

## Slide 2

## Slide 3

## COGA ASCERTAINMENT + PROTOCOL

- Proband recruited from inpatient or outpatient treatment units 		(n=9265/ 1,227 families)
- Must meet criteria for DSM-III-R _**alcohol dependence**_ and Feighner definite on direct interview with SSAGA
- _For genetic study: __***densely***__ affected families_
- Must have at least _**two additional 1**__**st**__** degree relatives**_ who also meet criteria for alcohol dependence on direct interview			 (n=2282/262 families)
- Assess additional biological relatives
- Control families recruited from the general population			 (n=1240/ 227 families)
- Blood sampling: DNA, cell lines
- Endophenotype: brain oscillations (EEG/ERP/ERO)

**Notes:**
COGA was designed as a family study based on densely affected families, to increase genetic loading. It is a very large archival database.
For genetic studies, a proband + 2 additional 1st degree relatives must meet COGA criteria (DSM-3R + Feighner definite) on direct interview, now DSM-4
Control families recruited from general pop to reflect base rates of all diseases 
(Today, we are also doing genetic studies using GWAS based on cases and controls from the COGA sample)
A unique feature of COGA is that we recorded brain oscillations (EEG,ERP,ERO) to be used as endophenotypes

## Endophenotypes

**Endophenotypes (or intermediate phenotypes) reflect more proximal effects of genes than diagnostic categories, and hence they provide a more powerful strategy in searching for genes involved in complex psychiatric disorders.**
**                                              ****(Gottesman & Gould, 2003)**
**“****Ideally, we should perform molecular genetic studies, **_***not on psychiatric diagnoses***_**, ****which reflect***** *****distal, variable effects of genes*****,***** ****but on **_***neurobiological measures***_** that reflect more proximal effects of genes involved in the **_**genetic predisposition**_** for psychiatric disorders.”****                                   ****(Tsuang & Faraone, 2000)**

## Advantages of using Quantitative Biological Risk Factors (ENDOPHENOTYPES)in search for genes in complex disorders

**Closer to gene action involved in the predisposition for the disorder**
**Genetically simpler than clinical endpoints**
**Quantitative traits provide more power to localize and characterize disease susceptibility genes**
**Identify relatives of affected individuals who would be considered unaffected with typical diagnostic systems including offspring at risk before the onset of illness**
**                             ****(reviewed by Porjesz and Begleiter, 2006)**

## Brain oscillations as endophenotypes

**Reflect **_**ensembles of neurons firing in synchrony**_** and represent the ****basic mechanism of neural communication****.**
**High frequencies:  are involved in short range communication **
**Low frequencies: longer range communication between brain areas.**
**Reflect the dynamic millisecond by millisecond balance between ****excitation**** and ****inhibition**** in the brain neural networks.**

**Notes:**
Skip part about high frequencies and low frequencies and say top and bottom bullet
You can say that they are divided into frequency bands: delta, theta, alpha, beta, gamma here or later on slide when say they are heritable.

## Brain oscillations as endophenotypes

_**Resting**_**: eyes closed EEG**
_**Active**_**: during sensory + cognitive tasks**
**	**_**E**_**vent **_**R**_**elated **_**P**_**otentials (ERP) **
**	**_**E**_**vent **_**R**_**elated **_**O**_**scillations (ERO)**

**Selected brain oscillations that differentiate between**** *****alcoholics***** ****and controls, and**** *****high risk***** *****offspring***** and controls**

**Notes:**
We recorded EEG in both resting states and while the individual is engaged in an active task
Selected brain oscillations that differentiate between alcoholics and controls, and high risk offspring and controls

## Brain oscillations as endophenotypes

**Brain oscillations are** _**highly heritable**_

| Frequency band | Mean h2 (Mz/Dz) |
| --- | --- |
| Delta   (1.5-3.5 Hz) | 76% |
| Theta   (4-7.5 Hz) | 89% |
| Alpha   (8-12.5 Hz) | 89% |
| Beta     (13-25 Hz) | 86% |

**(Van Beijsterveldt et al., 1996)**

**They are under ****genetic control**** and are modulated by genes controlling neurotransmitters in the brain.**

**Notes:**
To be considered as endophenotype, certain criteria must be met, the most important of which is that it be heritable.

## Increased resting beta power in abstinent alcoholics + offspring at high risk

**   ****Antecedes development of alcoholism: ****“****trait****”**** not “state” measure**
**   ****Index of ****CNS disinhibition****: involved in genetic predisposition toward alcohol dependence**
**   ****Provides good endophenotype**

_**HR (high risk) minus LR (low risk) Beta power:**_** **
**(Rangaswamy et al., 2002; 2004)**

**       ****β****1      ****β****2       ****β****3**

**            ****β****1**

**            ****β****2      **

**            ****β****3   **

**Alcoholic vs Control**

**Notes:**
We have found that alcoholics have increased resting beta power, and have also found that high risk offspring of alcoholics in the COGA sample also have increased beta.
Increased beta is an index of CNS disinhibition, which we hypothesize to be involved in a genetic predisposition to develop alcohol dependence + related disorders
This indicates that it antecedes the development of alcoholism and (provides a trait not state measure)
Thus, it provides a good endophenotype to be used for genetic studies

## LINKAGE ANALYSIS RESTING EEG: BETA

**Porjesz et al., PNAS, 2002**

**LLD**
**Comb Lod=6.53**
**p<0.004  **

_**LINKAGE ANALYSIS RESTING EEG: BETA**_

**N=1553/250**

***GABRA2,***** *****GABRA4,***** *****GABRB1,***** *****GABRG1***

***GABRA2, GABRA4, GABRB1, GABRG1***

**Notes:**
When we did a total genome scan with resting beta, we found that we had significant linkage (LOD=>5) on chromosome 4 at a cluster of GABA-A receptor genes, and when we did a combined linkage-linkage disequilibrium test, the LOD went up to 6.53 and was highly significant for association, indicating that a gene in this cluster accounted for the linkage

## SNPs across the cluster of GABAA receptor genes Significant LD for SNPs only in GABRA2 β EEG linkage/disequilibrium due to GABRA2

**Homozygotes**** for the rarer genotype (15%) of the rs279836 SNP in the *****GABRA2***** gene have significantly ****increased EEG Beta 2**** compared to individuals with all other genotypes. (i.e. manifest ****more CNS disinhibition****)**

*** p< 0.0001**

- *

**Beta power**

**N= 220 743 499**

**rs279836 genotype**

**Notes:**
When we examined snps across the cluster of GABA-A receptor genes, we found that it was significant only for GABRA2, not any of the others
When we looked at the most significant snp, we found that individuals who were homozygous for the rarer genotype had significantly increased beta compared to those with the other genotypes.
We are currently doing a prospective study in COGA, and are examining adolescents and young adults with these risk genotypes, as they go through the age of risk.

## Beta-rhythum, CNS Disinhibition, GABA + Alcoholism

**Beta rhythm is due to balance in networks of excitatory pyramidal cells and inhibitory interneurons that involve GABA****A**** action.**
**Increased beta in alcoholics and high risk offspring indicates imbalance in excitation/inhibition (**_**CNS disinhibition**_**).**
**Alterations of GABA****A****-benzodiazepine receptors in alcoholics and high risk offspring  ****(e.g., Volkow et al., 1995; Abi-Dargham et al., 1998; reviewed by Krystal et al., 2006)**

**Notes:**
The GABAergic findings in human changed across time during the first month of sobriety, and these changes were strongly affected by cigarette smoking. 

## ENDOPHENOTYPE APPROACHSame GABRA2 receptor gene is also involved in risk for Alcohol and Other Substance Dependence, Conduct Disorder (COGA: Edenberg et al. 2004; Dick et al. 2006; Agrawal et al., 2006)

**	****This finding provides a biological hypothesis relating **_**CNS disinhibition**_** to genetic risk for alcoholism and related disorders:**
**Variations in the *****GABRA2***** receptor gene affect brain oscillations and level of neural excitation**
**Imbalance in excitation/inhibition **
_**CNS disinhibition**_** is involved in the genetic risk for alcoholism and related disorders**
**	****Independent replications: e.g., Covault et al. 2004, 2007; Lappalainen et al. 2005; Fehr et al. 2006; Soyka et al. 2007; Matthews et al., 2007**

**Notes:**
With this endophenotype approach in COGA, we found that the same GABRA2 gene is also involved in risk for alcohol dependence, and more recently for related disorders, substance dependence and conduct disorder
These findings provide a biological hypothesis relating CNS disinhibition for genetic risk for alcoholism and related disorders.
Significantly, our findings with GABRA2 have been replicated in many studies throughout the world, and continue to be replicated, which is very important for genetic studies in complex disorders.

## EEG COHERENCE

**Measure of cortical**** ****synchronization in neural networks ****(the phase consistency of electrodes over time)**
**Indexing the functional relation,**** ****communication****, between populations of neurons (coupling between brain regions)**
**Modulated by genes controlling neurotransmitter action as pacemaker in inhibitory circuits**
**Heritable ****(Chorlian et al., 2007) **

**MUTUAL**** ****COORDINATION:**

**PACEMAKER:**

**Notes:**
More recently, we have been looking at another measure in the resting EEG:  coherence
This is a measure of synchrony between neural networks in the brain and is an index of communication 

## EEG High Theta (6-7 Hz) Coherence between Alcoholics and Controls

**Significant increases in EEG high theta coherence in alcoholics, particularly posterior, at parietal-occipital regions**
**Similar findings in high risk**** ****offspring of alcoholics            ****	****	****(Chorlian, Rangaswamy,et al.,  2007)**

- N=120/group

**Notes:**
We have recently found that alcoholics manifest increased coherence in the high theta band (6-7 Hz), and have similar results in high risk offspring

## Linkage with Resting EEG High Theta (6-7 Hz) Coherence

**P4-O2 – ****P3-O1**

**SNPs across cluster of GABA-A receptor genes**

**(Rangaswamy, in preparation)**

_***GABRA2***__** **__**Association analysis**_

**Notes:**
When we did a whole genome linkage screen with this high theta phenotype, we again found that we had significant linkage at the same location on chromosome 4 at the cluster of GABA-A receptor genes.  
Association analyses (using MG and QPDT) indicated highly (give some numbers?) significant association for snps in GABRA2, but not any of the other genes in the cluster—more significant than the initial findings with beta power
If you leave out next slide, say GABAergic system is important in the function of local inhibitory circuits, which are essential for cortical synchronization, and seem to be aberrant in alcoholics.

## Significant linkage and association of EEG 

**high theta (6-7 Hz) coherence and *****CHRM2***** **
**(Muscarinic Acetylcholine Receptor M2)**

**CHRM2**

**Both the GABAergic and cholinergic systems are important in the function of local inhibitory circuits, which are essential for cortical synchronization.**
**Localizing genes helps unravel neural substrates.**
**Dysfunction in coherence in alcoholics and High Risk**

## P300 (P3) amplitude of the event-related potential (ERP) provides a good endophenotype for alcohol dependence and other disinhibitory disorders

**Reduced P300 amplitude in abstinent alcoholics and high-risk offspring**
**Does not recover with prolonged abstinence**
**Precedes the development of alcoholism**

## P3 IS NOT A UNITARY PHENOMENON

**Multiple sources of activity: parietal and frontal cortex (including anterior cingulate).**
** ****The P300 is composed of different frequencies: primarily posterior delta (1-3 Hz) and **
**	****frontal theta (4-7 Hz).**
** **_**Theta**_** oscillations have been associated with *****memory processes *****and***** attention*****.  **_**Delta**_** oscillations are related to *****signal detection *****and***** decision making*****.**
-  These oscillations are **heritable** and are modulated by **genes** controlling neurotransmitters in the brain.
-  		 **endophenotypes for genetic analysis**

**Notes:**
Explain in the next slide
Say what on slide except 3rd bullet, which you can say on next slide

## Event-Related Potential (ERP) vs. Event-Related Oscillation (ERO)

****** ****This figure depicts grand-averaged ERP waveforms (left) and bandpass filtered ERP waveforms (right) with different frequency band ranges. **

_**Theta ERO**_**:**
** ****Memory processes**
** ****Attention**
** ****Fronto-limbic or **
**cortico-hippocampal interactions**

_**Delta ERO**_**:**
** ****Decision making**
** ****Generated by cortico-cortical interactions**
** ****Prominent after target stimuli**

## Theta and Delta EROs underlying P3 are reduced in alcoholics

**4-7Hz**

**1-3Hz**

**(Jones et al., 2006)**

**Theta and Delta EROs underlying P3 are reduced in alcoholics**

## Theta and Delta EROs underlying P3 are reduced in offspring of alcoholics in COGA

**Low Risk**
**(LR)**

**Theta and Delta EROs are more sensitive than P3 in discriminating between HR and LR.**
**                                         ****(Rangaswamy et al., 2007)**

**High Risk**
**(HR)**

**Theta and Delta EROs underlying P3 are reduced in offspring of alcoholics in COGA**

**THETA**

**DELTA**

## Significant linkage on Chromosome 7 with frontal Theta ERO to visual targets

***CHRM2***

**(Jones et al., 2004)**

****

- Waves 1& 2, N=1320/240

**Notes:**
When we did a total genome screen using the frontal theta ERO phenotype to targets in our visual P3 paradigm, we found significant linkage on chromosome 7 in a region where there is a cholinergic muscarinic receptor gene, CHRM2, under the peak.

## THETA ERO (frontal)

_**THETA ERO (frontal)**_

_**DELTA ERO (**__**Parietal-occipital**__**)**_

_**Association of 27 SNPs within and flanking **__***CHRM2***__** gene in Caucasian families**_
- (Measured Genotype + QPDT)

**Cholinergic system modulates P3**
**M2 receptors inhibit presynaptic release of acetylcholine**
**   ****->**_**inhibition of irrelevant networks**_
**Theta + delta depend on level of acetylcoholine (muscarinic activation)**

**(Jones et al., 2004; 2006)**

## EVIDENCE FROM COGA PROJECT THAT CHRM2 GENE INVOLVED IN CLINICAL DIAGNOSES

**Because of role of muscarinic cholinergic 2 receptor gene,*****CHRM2,***** in brain oscillations (endophenotype), evaluated whether *****CHRM2***** involved in risk for alcoholism**
**Significant linkage and association with DSM-IV alcohol dependence + major depressive disorder ****(Wang et al., 2004)**
**Comorbid alcohol and drug dependence—more severe form of disorder ****(Dick et al., 2007)**
**Replication by other groups**
***CHRM2***** gene predisposes to alcohol dependence, drug dependence and affective disorders ****(Luo et al., 2005)**

**Notes:**
Association of the CHRM2 gene with major depression in women (Comings et al., 2002)

## Significant linkage on Chromosome 7 with frontal Theta ERO to visual targets

***CHRM2***

****

****

***GRM8***

- F4 max=3.72
- at 162 cM

- N=1320/240

- Waves 1& 2

***GRM8 *****chr 7q31.3-q32.1 (mGluR8)**

**Jones et al., 2004**

## Glutamate and EROs

**The major neurochemical substrates contributing to theta and delta rhythms and P3 involve strong GABAergic, cholinergic and glutamatergic system interactions. **
**We already have evidence that a cholinergic muscarinic receptor gene (*****CHRM2*****) is involved in event-related theta oscillations underlying the P3. **
**To assess the potential association between SNPs in a glutamate receptor gene and the quantitative trait of event-related theta band energy during processing of target visual signals.**

## GRM8 chr 7q31.3-q32.1 (mGluR8)

**The *****GRM8***** is a member of the Group III metabotropic glutamate receptors (*****GRM4*****, *****GRM6*****, *****GRM7***** and *****GRM8*****), which are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.**
**Substances acting as agonists of group III mGlu receptors were shown to produce an anxiolytic-like effect after intrahippocampal administration to rats.**
**                                              ****(Palucha and others 2004)**
**Administration of the mGlu8 receptor agonist has also been shown to suppress alcohol self-administration and cue-induced reinstatement of alcohol seeking in preclinical study.**
**                                              ****(Backstrom and Hyytia 2005)**** **

## Association of SNPs in GRM8 with theta EROs 

| SNP | b.p.
position | Loca-
tion | F3 | Frontal
Fz | F4 | C3 | Central
 Cz | C4 | P3 | Parietal
 Pz | P4 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| RS2402816 | 125785127 | intron7 | 0.093351 | 0.252568 | 0.093892 | 0.118173 | 0.14569 | 0.024175 | 0.379564 | 0.149178 | 0.158817 |
| RS2299459 | 125789319 | intron7 | 0.000242 | 0.000858 | 0.000135 | 0.000225 | 0.00027 | 0.00005 | 0.000658 | 0.000318 | 0.001146 |
| RS1158720 | 125802257 | intron7 | 0.000553 | 0.0016 | 0.000389 | 0.000356 | 0.00068 | 0.000191 | 0.001271 | 0.002041 | 0.006588 |
| RS769198 | 125843397 | Exon7 | 0.148956 | 0.164083 | 0.190267 | 0.176354 | 0.14539 | 0.22199 | 0.339653 | 0.254789 | 0.222664 |
| RS7797602 | 125881778 | intron6 | 0.000151 | 0.000318 | 0.000087 | 0.000275 | 0.00036 | 0.000103 | 0.00096 | 0.001005 | 0.003023 |
| RS2402820 | 125891649 | intron6 | 0.025128 | 0.049439 | 0.012641 | 0.074566 | 0.14073 | 0.041059 | 0.058175 | 0.077618 | 0.084461 |
| RS1074728 | 125906795 | intron6 | 0.096584 | 0.216603 | 0.114742 | 0.091394 | 0.09409 | 0.021838 | 0.134333 | 0.074237 | 0.15928 |
| RS4731323 | 125917981 | intron6 | 0.005013 | 0.012996 | 0.006684 | 0.005948 | 0.00978 | 0.002702 | 0.011203 | 0.006601 | 0.015576 |
| RS1361991 | 125932593 | intron6 | 0.214853 | 0.360647 | 0.380487 | 0.319222 | 0.21013 | 0.127477 | 0.579042 | 0.29104 | 0.27828 |
| RS2299495 | 125950918 | intron6 | 0.085667 | 0.112744 | 0.1531 | 0.026541 | 0.04064 | 0.145957 | 0.011396 | 0.028879 | 0.032381 |
| RS2299498 | 125951878 | intron6 | 0.486164 | 0.767491 | 0.647005 | 0.797503 | 0.80816 | 0.418746 | 0.785061 | 0.556374 | 0.379391 |
| RS10256873 | 125962243 | intron6 | 0.935112 | 0.735431 | 0.971051 | 0.51099 | 0.47389 | 0.981567 | 0.269095 | 0.385705 | 0.586868 |
| RS1361995 | 125966008 | intron6 | 0.00035 | 0.000996 | 0.000603 | 0.000133 | 0.00014 | 0.000057 | 0.000532 | 0.000298 | 0.000768 |
| RS10487457 | 125970841 | intron6 | 0.001119 | 0.002741 | 0.001726 | 0.000218 | 0.00042 | 0.000121 | 0.001015 | 0.000857 | 0.002111 |
| RS10487459 | 125972206 | intron6 | 0.000718 | 0.002283 | 0.001359 | 0.000228 | 0.0003 | 0.000098 | 0.001097 | 0.000693 | 0.001935 |
|  |  |  |  |  |  |  |  |  |  |  |  |
|  | Significance Level: |  |  | p<0.05 | p<0.01 | P<0.001 | p<0.0001 |  |  |  |  |

**Data present the p-value of the FBAT.**
**                  ****(Chen et al., under revision)**

## Association of SNPs in GRM8 with Alcohol Dependence 

| SNP | b.p. position | location | DSM-IV | ICD-10 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| RS2402816 | 125785127 | intron7 | 0.096978 | 0.122487 |  |  |
| RS2299459 | 125789319 | intron7 | 0.723224 | 0.938865 |  |  |
| RS1158720 | 125802257 | intron7 | 0.713209 | 0.940422 |  |  |
| RS769198 | 125843397 | Exon7 | 0.947598 | 0.936858 |  |  |
| RS7797602 | 125881778 | intron6 | 0.605235 | 0.781739 |  |  |
| RS2402820 | 125891649 | intron6 | 0.683155 | 0.465489 |  |  |
| RS1074728 | 125906795 | intron6 | 0.133743 | 0.200811 |  |  |
| RS4731323 | 125917981 | intron6 | 0.149046 | 0.532717 |  |  |
| RS1361991 | 125932593 | intron6 | 0.017395 | 0.032223 |  |  |
| RS2299495 | 125950918 | intron6 | 0.489521 | 0.77779 |  |  |
| RS2299498 | 125951878 | intron6 | 0.024236 | 0.046078 |  |  |
| RS10256873 | 125962243 | intron6 | 0.038377 | 0.203827 |  |  |
| RS1361995 | 125966008 | intron6 | 0.058406 | 0.036781 |  |  |
| RS10487457 | 125970841 | intron6 | 0.070355 | 0.03734 |  |  |
| RS10487459 | 125972206 | intron6 | 0.072757 | 0.040956 |  |  |
|  |  |  |  |  |  |  |
|  | Significance Level: |  | p<0.05 | p<0.01 | P<0.001 | p<0.0001 |

**Data present the p-value of the FBAT.**
**                  ****(Chen et al., under revision)**

## Association of SNPs in GRM8 with theta EROs at Frontal, Central, and Parietal Regions and Alcohol Dependence 

| SNP | b.p. position | Loca-
tion | F3 | FrontalFz | F4 | C3 | CentrlCz | C4 | P3 | ParietlPz | P4 | DSM-IV | ICD-10 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| RS2402816 | 125785127 | intron7 | 0.093351 | 0.252568 | 0.093892 | 0.118173 | 0.145693 | 0.024175 | 0.379564 | 0.149178 | 0.158817 | 0.096978 | 0.122487 |
| RS2299459 | 125789319 | intron7 | 0.000242 | 0.000858 | 0.000135 | 0.000225 | 0.000272 | 0.00005 | 0.000658 | 0.000318 | 0.001146 | 0.723224 | 0.938865 |
| RS1158720 | 125802257 | intron7 | 0.000553 | 0.0016 | 0.000389 | 0.000356 | 0.000679 | 0.000191 | 0.001271 | 0.002041 | 0.006588 | 0.713209 | 0.940422 |
| RS769198 | 125843397 | Exon7 | 0.148956 | 0.164083 | 0.190267 | 0.176354 | 0.145386 | 0.22199 | 0.339653 | 0.254789 | 0.222664 | 0.947598 | 0.936858 |
| RS7797602 | 125881778 | intron6 | 0.000151 | 0.000318 | 0.000087 | 0.000275 | 0.000363 | 0.000103 | 0.00096 | 0.001005 | 0.003023 | 0.605235 | 0.781739 |
| RS2402820 | 125891649 | intron6 | 0.025128 | 0.049439 | 0.012641 | 0.074566 | 0.140728 | 0.041059 | 0.058175 | 0.077618 | 0.084461 | 0.683155 | 0.465489 |
| RS1074728 | 125906795 | intron6 | 0.096584 | 0.216603 | 0.114742 | 0.091394 | 0.094091 | 0.021838 | 0.134333 | 0.074237 | 0.15928 | 0.133743 | 0.200811 |
| RS4731323 | 125917981 | intron6 | 0.005013 | 0.012996 | 0.006684 | 0.005948 | 0.009776 | 0.002702 | 0.011203 | 0.006601 | 0.015576 | 0.149046 | 0.532717 |
| RS1361991 | 125932593 | intron6 | 0.214853 | 0.360647 | 0.380487 | 0.319222 | 0.210134 | 0.127477 | 0.579042 | 0.29104 | 0.27828 | 0.017395 | 0.032223 |
| RS2299495 | 125950918 | intron6 | 0.085667 | 0.112744 | 0.1531 | 0.026541 | 0.040644 | 0.145957 | 0.011396 | 0.028879 | 0.032381 | 0.489521 | 0.77779 |
| RS2299498 | 125951878 | intron6 | 0.486164 | 0.767491 | 0.647005 | 0.797503 | 0.808164 | 0.418746 | 0.785061 | 0.556374 | 0.379391 | 0.024236 | 0.046078 |
| RS10256873 | 125962243 | intron6 | 0.935112 | 0.735431 | 0.971051 | 0.51099 | 0.473886 | 0.981567 | 0.269095 | 0.385705 | 0.586868 | 0.038377 | 0.203827 |
| RS1361995 | 125966008 | intron6 | 0.00035 | 0.000996 | 0.000603 | 0.000133 | 0.000141 | 0.000057 | 0.000532 | 0.000298 | 0.000768 | 0.058406 | 0.036781 |
| RS10487457 | 125970841 | intron6 | 0.001119 | 0.002741 | 0.001726 | 0.000218 | 0.00042 | 0.000121 | 0.001015 | 0.000857 | 0.002111 | 0.070355 | 0.03734 |
| RS10487459 | 125972206 | intron6 | 0.000718 | 0.002283 | 0.001359 | 0.000228 | 0.000297 | 0.000098 | 0.001097 | 0.000693 | 0.001935 | 0.072757 | 0.040956 |
|  |  |  |  |  |  |  |  |  |  |  |  |  |  |
|  | Significance Level: |  |  | p<0.05 | p<0.01 | p<0.001 | p<0.0001 |  |  |  |  |  |  |

**Data present the p-value of the FBAT.**
**                  ****(Chen et al., under revision)**

## Low visual P3 amplitude is not specific to risk of alcohol dependence but is characteristic of many disinhibitory conditions

**Substance abuse **
**Antisocial Personality Disorder**
**Conduct disorder**
**Attention Deficit Hyperactivity Disorder**
** **
**                            ****(Reviewed by e.g., ****Porjesz et al., 2005)**

## Is there a common genetic diathesis ?

**Alcohol dependence is a**
**disorder of disinhibition**
**Characterized by ****disturbed impulse regulation, ****and “termination pathology”**
**    ****i.e. inability to terminate behavior at an appropriate point in time.**
**These traits are **_**not unique to alcoholism**_**, but are fundamental to other psychiatric disorders.**

**Clinical manifestations of disinhibition:**
**Impulsivity**
**Alcohol dependence**
**Drug dependence**
**Conduct disorder**
**Oppositional disorder**
**Mania**
**Attention Deficit Hyperactivity Disorder**

## Externalizing

**Externalizing**

**Alcohol**
**Dependence**

**Substance**
**Dependence**

**Antisocial**
**Personality**

**Conduct**
**Disorder**

**OVERLAPPING GENETIC COMPONENTS OF DISINHIBITORY PSYCHIATRIC DISORDERS**

**(Kendler et al., 2003)**

**Common underlying genetic liability involving impulse control**

**Notes:**
Recent evidence suggests that this class of disinhibitory disorders have a similar underlying genetic diathesis, with each disorder representing a different expression of the same underlying genetic liability.

## Alcohol-dependent subjects show an increased level of impulsivity trait (BIS)  

**A****lcohol-dependent subjects show**** an increased level of ****impulsivity**** trait (BIS)****  **

**Significant negative correlations between VP3 amplitude and impulsivity.**

**Total score + Subscales:**
**NP= Non-Planning **
**MI= Motor Impulsiveness **
**CI= Cognitive Impulsiveness**
**    ****(Attentional Impulsiveness)****  **

**(Chen et al., 2007)**

## Alcoholics showed significantly reduced activation in anterior cingulate, cingulate gyrus, medial gyrus, and superior frontal gyrus with LORETA*  during the processing of visual targets  

**Controls**

**Alcoholics**

** ****High Impulsive subjects****, ****regardless of diagnosis****, showed significantly reduced activation during the processing of target visual signal in the ****same frontal regions.        ****(Chen et al., 2007)**

***low-resolution brain electromagnetic**
**tomography**

**Notes:**
Axial     Saggital     Coronal

## Conclusions

**Genetically influenced differences in susceptibility involve ****neural disinhibition**** and ****impulsivity.**
**Involves ****frontal lobe functions**
**Influences a **_**range of outcomes**_** including ****externalizing**** and ****mood disorders, alcoholism**** and ****abuse of other substances.**

## Conclusions (continued)

**These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders. **
**Many of the same genes important for the expression of the endophenotypes help in identification of genes that increase the susceptibility for risk of alcohol dependence and related disorders.**

## Acknowledgment

**The Collaborative Study on the Genetics of Alcoholism (COGA)**
**Co-Principal Investigators:**
**	****      ****	****B. Porjesz ****	****SUNY Downstate Medical Center ****	**
**    ****	****	****V. Hesselbrock  ****	****University of Connecticut**
**      ****	****H. Edenberg****	****Indiana University****	**
**	****	****L. Bierut ****	****Washington University**
**	**
**	****Nine different centers where data collection, analysis, and storage take place: **
**	****	****University of Connecticut**** (V. Hesselbrock)**
**	****	****Indiana University**** (H.J. Edenberg, J. Nurnberger Jr., P.M. Conneally, T. Foroud)**
**	****	****University of Iowa**** (S. Kuperman, R. Crowe)**
**	****	****SUNY Downstate**** (B. Porjesz)**
**	****	****Washington University in St. Louis**** (L. Bierut, A. Goate, J. Rice)**
**	****	****University of California at San Diego**** (M. Schuckit)**
**	****	****Howard University (R. Taylor)**
**	****	****Rutgers University (J. Tischfield)**
**	****	****Southwest Foundation (L. Almasy)**
**	****Zhaoxia Ren serves as the NIAAA Staff Collaborator.  This national collaborative study is supported by the NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). **
**	****In memory of Henri Begleiter and Theodore Reich, Principal and Co-Principal Investigators of COGA since its inception. We are indebted to their leadership in the establishment and nurturing of COGA, and acknowledge with great admiration their seminal scientific contributions to the field.**

-   **Dr. Andrew C. Chen receives support from the American Psychiatric Association/ American Psychiatric Institute for Research And Education/ NIMH PMRTP Award, 2006-2008**

## Visual Oddball Experiment

**The P300 represents a measure of CNS processing of salient stimulus information (including attention and memory). P3(00) reflects an index of CNS inhibition. **
**The low P3 amplitude indicates a state of disinhibition****.**

**Notes:**
This slide describes the Visual Oddball experiment.

3 visual stimuli are presented – target, novel and non-target - subjects are requested to press to rare target stimuli.  
EEG data re recorded at multiple electrode positions on the scalp.  
The salient Target condition stimulus elicits the P300 “wave” which a positive-going deflection approximately 300 ms.  The frequent Non-Target condition does not elicit the P300 wave. 

## The S-transform TFR

-  **Time-Frequency Representation (TFR) used to *****localize***** the spectral content of *****non-stationary***** time-series.**
** ****The S-transform TFR (Stockwell, 1996) is a *****generalization***** of the STFT (Portnoff, 1980) and an *****extension***** to the Continuous Wavelet Transform (Goupillaud, 1984).**
** ****The S-transform provides frequency dependent resolution (multi-resolution) while simultaneously localizing the complex components of the signal.**