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Wednesday, June 17, 2009

GABRR1 and GABRR2, encoding the GABA-A receptor subunits 1 and 2, are associated with alcohol dependence
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published Online: 17 Jun 2009

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 1 and 2 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 and a haplotype in GABRR2 was significantly overtransmitted to family members who met a broader definition of alcoholism as well as DSM-IV dependence.


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