GABRR1 and GABRR2, encoding the GABA-A receptor subunits ρ1 and ρ2, are associated with alcohol dependence

Xiaoling Xuei, Leah Flury-Wetherill, Danielle Dick, Alison Goate, Jay Tischfield, John Nurnberger, Marc Schuckit, John Kramer, Sam Kuperman, Victor Hesselbrock, Bernice Porjesz, Tatiana Foroud, Howard Edenberg

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 evaluationof the GABA receptor genes, weevaluated 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. Wegenotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcoholdependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associatedwith alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using amedian 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 signifi-cantly overtransmitted to familymembers whodid notmeet criteria for alcohol dependence (P<0.04), and a haplotype in GABRR2 was significantly overtransmitted to familymembers whomet a broader definition of alcoholism (P=0.002) as well as DSM-IV dependence (P=0.04).

Original languageEnglish
Pages (from-to)418-427
Number of pages10
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume153
Issue number2
DOIs
StatePublished - Mar 2010

Fingerprint

GABA-A Receptors
Alcoholism
Single Nucleotide Polymorphism
Haplotypes
Genes
Chromosomes, Human, Pair 16
GABA Receptors
Age of Onset
Diagnostic and Statistical Manual of Mental Disorders
gamma-Aminobutyric Acid

Keywords

  • Alcoholism
  • GABA-A receptor
  • Genetics
  • Rho subunit
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

GABRR1 and GABRR2, encoding the GABA-A receptor subunits ρ1 and ρ2, are associated with alcohol dependence. / Xuei, Xiaoling; Flury-Wetherill, Leah; Dick, Danielle; Goate, Alison; Tischfield, Jay; Nurnberger, John; Schuckit, Marc; Kramer, John; Kuperman, Sam; Hesselbrock, Victor; Porjesz, Bernice; Foroud, Tatiana; Edenberg, Howard.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 153, No. 2, 03.2010, p. 418-427.

Research output: Contribution to journalArticle

Xuei, Xiaoling ; Flury-Wetherill, Leah ; Dick, Danielle ; Goate, Alison ; Tischfield, Jay ; Nurnberger, John ; Schuckit, Marc ; Kramer, John ; Kuperman, Sam ; Hesselbrock, Victor ; Porjesz, Bernice ; Foroud, Tatiana ; Edenberg, Howard. / GABRR1 and GABRR2, encoding the GABA-A receptor subunits ρ1 and ρ2, are associated with alcohol dependence. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2010 ; Vol. 153, No. 2. pp. 418-427.
@article{ed68fcf1de6a48ce988a244d046cbda9,
title = "GABRR1 and GABRR2, encoding the GABA-A receptor subunits ρ1 and ρ2, 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 evaluationof the GABA receptor genes, weevaluated 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. Wegenotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcoholdependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associatedwith alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using amedian 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 signifi-cantly overtransmitted to familymembers whodid notmeet criteria for alcohol dependence (P<0.04), and a haplotype in GABRR2 was significantly overtransmitted to familymembers whomet a broader definition of alcoholism (P=0.002) as well as DSM-IV dependence (P=0.04).",
keywords = "Alcoholism, GABA-A receptor, Genetics, Rho subunit, Single nucleotide polymorphism",
author = "Xiaoling Xuei and Leah Flury-Wetherill and Danielle Dick and Alison Goate and Jay Tischfield and John Nurnberger and Marc Schuckit and John Kramer and Sam Kuperman and Victor Hesselbrock and Bernice Porjesz and Tatiana Foroud and Howard Edenberg",
year = "2010",
month = "3",
doi = "10.1002/ajmg.b.30995",
language = "English",
volume = "153",
pages = "418--427",
journal = "American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics",
issn = "1552-4841",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - GABRR1 and GABRR2, encoding the GABA-A receptor subunits ρ1 and ρ2, are associated with alcohol dependence

AU - Xuei, Xiaoling

AU - Flury-Wetherill, Leah

AU - Dick, Danielle

AU - Goate, Alison

AU - Tischfield, Jay

AU - Nurnberger, John

AU - Schuckit, Marc

AU - Kramer, John

AU - Kuperman, Sam

AU - Hesselbrock, Victor

AU - Porjesz, Bernice

AU - Foroud, Tatiana

AU - Edenberg, Howard

PY - 2010/3

Y1 - 2010/3

N2 - 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 evaluationof the GABA receptor genes, weevaluated 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. Wegenotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcoholdependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associatedwith alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using amedian 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 signifi-cantly overtransmitted to familymembers whodid notmeet criteria for alcohol dependence (P<0.04), and a haplotype in GABRR2 was significantly overtransmitted to familymembers whomet a broader definition of alcoholism (P=0.002) as well as DSM-IV dependence (P=0.04).

AB - 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 evaluationof the GABA receptor genes, weevaluated 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. Wegenotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcoholdependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associatedwith alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using amedian 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 signifi-cantly overtransmitted to familymembers whodid notmeet criteria for alcohol dependence (P<0.04), and a haplotype in GABRR2 was significantly overtransmitted to familymembers whomet a broader definition of alcoholism (P=0.002) as well as DSM-IV dependence (P=0.04).

KW - Alcoholism

KW - GABA-A receptor

KW - Genetics

KW - Rho subunit

KW - Single nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=77349089752&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77349089752&partnerID=8YFLogxK

U2 - 10.1002/ajmg.b.30995

DO - 10.1002/ajmg.b.30995

M3 - Article

VL - 153

SP - 418

EP - 427

JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

SN - 1552-4841

IS - 2

ER -