Mutation screen of the GAD2 gene and association study of alcoholism in three populations.
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.
Lappalainen
Jaakko
J
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. jaakko.lappalainen@yale.edu
Krupitsky
Evgeny
E
Kranzler
Henry R
HR
Luo
Xingguang
X
Remizov
Mikhail
M
Pchelina
Sofia
S
Taraskina
Anastaisa
A
Zvartau
Edwin
E
Räsanen
Pirkko
P
Makikyro
Taru
T
Somberg
Lucia K
LK
Krystal
John H
JH
Stein
Murray B
MB
Gelernter
Joel
J
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*
D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2