title: Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.
abstract: Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P=.000000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.
authors.affiliation: Indiana University School of Medicine, Indianapolis 46202, USA. edenberg@iupui.edu
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xuei
authors.forename: Huijun
authors.initials: H
authors.lastname: Tian
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Lance O
authors.initials: LO
authors.lastname: Bauer
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Crowe
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.forename: Kevin
authors.initials: K
authors.lastname: Jones
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kwon
authors.forename: Ting-Kai
authors.initials: TK
authors.lastname: Li
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.forename: Sean J
authors.initials: SJ
authors.lastname: O'Connor
authors.forename: Theodore
authors.initials: T
authors.lastname: Reich
authors.forename: John
authors.initials: J
authors.lastname: Rice
authors.forename: Marc A
authors.initials: MA
authors.lastname: Schuckit
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Henri
authors.initials: H
authors.lastname: Begleiter
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D004569:Electroencephalography; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics*
chemical_list: C484841:GABRA2 protein, human; D005819:Genetic Markers; D011963:Receptors, GABA-A