GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence.

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2010 Mar 05

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The genes encoding several GABA-A receptor subunits, including GABRA2, have been associated with alcoholism, suggesting that variations in gaba signaling contribute to risk. Therefore, as part of a comprehensive evaluation of the GABA receptor genes, we evaluated the potential association of GABRR1 and GABRR2, which encode the rho1 and rho2 subunits of the pentameric GABA-A/GABA-C receptors. GABRR1 and GABRR2 lie in a head to tail orientation spanning 137 kb on chromosome 6q14-16. We genotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95 kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcohol-dependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associated with alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using a median split for age of onset suggests that the association is strongest when the analysis is focused upon those with earlier onset of alcohol dependence. Haplotypes in each gene were significantly overtransmitted to family members who did not meet criteria for alcohol dependence (P < 0.04), and a haplotype in GABRR2 was significantly overtransmitted to family members who met a broader definition of alcoholism (P = 0.002) as well as DSM-IV dependence (P = 0.04). (c) 2009 Wiley-Liss, Inc.

Citation

Xiaoling Xuei, Leah Flury-Wetherill, Danielle Dick, Alison Goate, Jay Tischfield, John Nurnberger, Marc Schuckit, John Kramer, Sam Kuperman, Victor Hesselbrock, Bernice Porjesz, Tatiana Foroud, Howard J Edenberg. GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2010 Mar 05;153B(2):418-427