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GABRR1 and GABRR2 , encoding the GABA‐A receptor subunits ρ1 and ρ2, are associated with alcohol dependence
Author(s) -
Xuei Xiaoling,
FluryWetherill Leah,
Dick Danielle,
Goate Alison,
Tischfield Jay,
Nurnberger John,
Schuckit Marc,
Kramer John,
Kuperman Sam,
Hesselbrock Victor,
Porjesz Bernice,
Foroud Tatiana,
Edenberg Howard J.
Publication year - 2010
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30995
Subject(s) - single nucleotide polymorphism , haplotype , alcohol dependence , genetics , snp , gene , biology , alcohol , allele , genotype , biochemistry
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 ρ1 and ρ2 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). © 2009 Wiley‐Liss, Inc.