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

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

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics (2006-10-13)
Jaakko Lappalainen, Evgeny Krupitsky, Henry R Kranzler, Xingguang Luo, Mikhail Remizov, Sofia Pchelina, Anastaisa Taraskina, Edwin Zvartau, Pirkko Räsanen, Taru Makikyro, Lucia K Somberg, John H Krystal, Murray B Stein, Joel Gelernter

Synaptic actions of gamma-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.