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Sunday, March 4, 2007

Mutation screen of the GAD2 gene and association study of alcoholism in three populations

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Volume 144B, Issue 2 , Pages 183 - 192



Jaakko Lappalainen 1 2 *,
Evgeny Krupitsky 3,
Henry R. Kranzler 4,
Xingguang Luo 1 2,
Mikhail Remizov 3,
Sofia Pchelina 3,
Anastaisa Taraskina 3,
Edwin Zvartau 3,
Pirkko Räsanen 5,
Taru Makikyro 5,
Lucia K. Somberg 1 2,
John H. Krystal 1 2,
Murray B. Stein 6,
Joel Gelernter 1 2

1Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
2VA Connecticut Healthcare System, West Haven, Connecticut
3St. Petersburg State Pavlov Medical University, St. Petersburg, Russia
4Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut
5Department of Psychiatry, University of Oulu, Oulu, Finland
6Department of Psychiatry, University of California, San Diego, California
email: Jaakko Lappalainen (jaakko.lappalainen@yale.edu)

*Correspondence to Jaakko Lappalainen, Yale University, VA Connecticut Healthcare System, Psychiatry 116A2, 950 Campbell Ave, West Haven CT 06516.

Funded by:
National Institutes of Health; Grant Number: K08 AA13732, R01 AA11330, P50 AA12870, M01 RR06192, K05 AA14906, K24 AA13736, R01 AA011321-04, P50-AA03510, K24 MH64122
Alcoholic Beverage Medical Research Foundation (ABMRF)
US Department of Veterans Affairs [VA Alcohol Research Center, VA Mental Illness Research, Education and Clinical Center (VA MIRECC), and VA Veterans Research Enhancement Award Program (VA REAP)]
Ethel F. Donaghue Women's Health Investigator Program at Yale


Abstract
Synaptic actions of -amino butyric acid (GABA) have been implicated in many facets of ethanol's effects and risk for alcoholism.

We examined whether variation in glutamate decarboxylase-2 (GAD2), a gene encoding for a major enzyme in the synthesis of GABA, contributes to risk of alcohol dependence (AD).

We screened GAD2 for sequence variants using dHPLC in a population of 96 individuals.

Several single nucleotide polymorphisms (SNPs), including four rare non-synonymous polymorphisms, were identified. Thirteen SNPs located in the GAD2 gene were genotyped in a sample of 113 Russian males with AD and 100 Russian male controls.

These analyses revealed a modest association between the functional GAD2 -243 A > G SNP (rs2236418) and AD (allele P = 0.038, genotype P = 0.008). An additional sample of 138 Russian males with AD were genotyped for the GAD2 -243 A > G.

These analyses supported an association of this polymorphism with AD (combined sample allele P = 0.038, genotype P = 0.0009).

We extended these findings to additional populations: a sample of 538 college students assessed using the AUDIT and a sample of European-American (EA) AD subjects (n = 235) and controls (n = 310).

Analyses in these populations did not support a role for GAD2 in alcoholism.

In summary, the results of an extensive search for an association of GAD2 with AD suggest that variation in GAD2 is not a major risk factor for AD in EAs.

The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD.
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