GABRR1andGABRR2, encoding the GABA‐A receptor subunits ρ1 and ρ2, are associated with alcohol dependence

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Abstract
The genes encoding several GABA‐A receptor subunits, includingGABRA2, 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 ofGABRR1andGABRR2, which encode the ρ1 and ρ2 subunits of the pentameric GABA‐A/GABA‐C receptors.GABRR1andGABRR2lie 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 ofGABRR2and 95 kb downstream ofGABRR1, in a sample of 1923 European Americans from 219 multiplex alcohol‐dependent families. Family‐based association analyses demonstrated that SNPs in bothGABRR1andGABRR2were significantly associated with alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) inGABRR2. 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 inGABRR2was significantly overtransmitted to family members who met a broader definition of alcoholism (P = 0.002) as well as DSM‐IV dependence (P = 0.04).
Funding Information
  • National Institute on Alcohol Abuse and Alcoholism (NIAAA) (U10AA008401)
  • National Institute on Drug Abuse (NIDA)
  • Indiana Genomics Initiative of Indiana University (INGEN®)
  • The Lilly Endowment, Inc.