GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence.
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).
Xuei
Xiaoling
X
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
Flury-Wetherill
Leah
L
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Dick
Danielle
D
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
Goate
Alison
A
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Tischfield
Jay
J
Department of Genetics, Rutgers University, Piscataway, New Jersey.
Nurnberger
John
J
Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
Schuckit
Marc
M
Department of Psychiatry, University of California-San Diego, San Diego, California.
Kramer
John
J
Psychiatry Research, University of Iowa College of Medicine, Iowa City, Iowa.
Kuperman
Sam
S
Division of Child Psychiatry, University of Iowa Hospitals, Iowa City, Iowa.
Hesselbrock
Victor
V
Department of Psychiatry, University of Connecticut Health Center, Farmington, Connecticut.
Porjesz
Bernice
B
Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Medical Center, Brooklyn, New York.
Foroud
Tatiana
T
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Edenberg
Howard J
HJ
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
D017668:Age of Onset; D000437:Alcoholism / Q000235:genetics / Q000378:metabolism*; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
C547868:GABRR1 protein, human; C106350:GABRR2 protein, human; D011963:Receptors, GABA-A