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GABRG1 and GABRA2 Variation Associated with Alcohol Dependence in African Americans

Authors

  • Chupong Ittiwut,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Bao-Zhu Yang,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Henry R. Kranzler,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Raymond F. Anton,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Rungnapa Hirunsatit,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Roger D. Weiss,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Jonathan Covault,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Lindsay A. Farrer,

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Joel Gelernter

    1. From the Department of Psychiatry (CI, B-ZY, RH, JG), Yale University School of Medicine, New Haven, Connecticut; VA CT Healthcare System (CI, B-ZY, RH, JG), West Haven, Connecticut; Chula GenePRO Center (CI), Faculty of Medicine, Chulalongkorn University, Bangkok Thailand; Departments of Psychiatry and Genetics and Developmental Biology (HRK, JC), University of Connecticut School of Medicine, Farmington, Connecticut; Department of Psychiatry and Behavioral Sciences (RFA), Medical University of South Carolina, Charleston, South Carolina; The Special Investigation Division (RH), Institute of Pathology, Bangkok, Thailand; McLean Hospital & Harvard Medical School (RDW), Belmont, Massachusetts; Departments of Medicine, Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (LAF), Boston University Schools of Medicine and Public Health, Boston, Massachusetts; and Departments of Genetics and Neurobiology (JG), Yale University School of Medicine, New Haven, Connecticut.
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  • Chupong Ittiwut and Bao-Zhu Yang contributed equally to this work.

Reprint requests: Joel Gelernter, MD, Yale University School of Medicine, VA Psychiatry 116A2, 950 Campbell Avenue, West Haven, CT 06516; Tel.: 203-932-5711 ext. 3590; Fax: 203-937-4741; E-mail: joel.gelernter@yale.edu

Abstract

Background: GABRG1 and GABRA2, genes that encode the γ1 and α2 subunits, respectively, of the GABA-A receptor, are located in a cluster on chromosome 4p. Association of alcohol dependence (AD) with markers located at the 3′ region of GABRA2 has been replicated in several studies, but recent studies suggested the possibility that the signal may be attributable to the adjacent gene, GABRG1, located 90 kb distant in the 3′ direction. Owing to strong linkage disequilibrium (LD) in European Americans (EAs), the origin, or origins, of the association signal is very difficult to discern, but our previous population-based study suggested that decreased LD across the GABRG1GABRA2 region in African Americans (AAs) may be useful for fine mapping and resolution of the association signal in that population.

Methods:  To examine these associations in greater detail, we genotyped 13 single nucleotide polymorphisms (SNPs) spanning GABRG1 and GABRA2 in 380 AAs with AD and in 253 AA controls.

Results:  Although there was no association between any individual SNP and AD, a highly significant difference was shown between AD subjects and controls in the frequency of a 3-SNP GABRA2 haplotype (global p = 0.00029). A similar level of significance was obtained in 6-SNP haplotypes that combined tagging SNPs from both genes (global = 0.00994). High statistical significance was also shown with a 6-SNP haplotype (T-G-C-G-T-A), p = 0.0033. The T-G-C-G-T-A haplotype contains the most significant GABRA2 3-SNP haplotype (= 0.00019), G-T-A.

Conclusions:  These findings reflect the interrelationship between these 2 genes and the likelihood that risk loci exist in each of them. Study of an AA population allowed evaluation of these associations at higher genomic resolution than is possible in a EA population, owing to the much lower LD across these loci in AAs.

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