title: GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence.
abstract: 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).
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xuei
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Leah
authors.initials: L
authors.lastname: Flury-Wetherill
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Dick
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, New Jersey.
authors.forename: Jay
authors.initials: J
authors.lastname: Tischfield
authors.affiliation: Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: John
authors.initials: J
authors.lastname: Nurnberger
authors.affiliation: Department of Psychiatry, University of California-San Diego, San Diego, California.
authors.forename: Marc
authors.initials: M
authors.lastname: Schuckit
authors.affiliation: Psychiatry Research, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: John
authors.initials: J
authors.lastname: Kramer
authors.affiliation: Division of Child Psychiatry, University of Iowa Hospitals, Iowa City, Iowa.
authors.forename: Sam
authors.initials: S
authors.lastname: Kuperman
authors.affiliation: Department of Psychiatry, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.affiliation: Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Medical Center, Brooklyn, New York.
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: 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.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
mesh_terms: 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*
chemical_list: C547868:GABRR1 protein, human; C106350:GABRR2 protein, human; D011963:Receptors, GABA-A