title: Mutation screen of the GAD2 gene and association study of alcoholism in three populations.
abstract: 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.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. jaakko.lappalainen@yale.edu
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lappalainen
authors.forename: Evgeny
authors.initials: E
authors.lastname: Krupitsky
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.forename: Xingguang
authors.initials: X
authors.lastname: Luo
authors.forename: Mikhail
authors.initials: M
authors.lastname: Remizov
authors.forename: Sofia
authors.initials: S
authors.lastname: Pchelina
authors.forename: Anastaisa
authors.initials: A
authors.lastname: Taraskina
authors.forename: Edwin
authors.initials: E
authors.lastname: Zvartau
authors.forename: Pirkko
authors.initials: P
authors.lastname: Räsanen
authors.forename: Taru
authors.initials: T
authors.lastname: Makikyro
authors.forename: Lucia K
authors.initials: LK
authors.lastname: Somberg
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Murray B
authors.initials: MB
authors.lastname: Stein
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000437:Alcoholism / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013334:Students; D014481:United States; D044465:White People / Q000235:genetics*
chemical_list: D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2