Association Analysis of Sequence Variants of the GABAAα6, β2, and γ2 Gene Cluster and Alcohol Dependence

Authors

  • Thomas Sander,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • David Ball,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • Robin Murray,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • Jaimin Patel,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • Jerzy Samochowiec,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • Georg Winterer,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • Hans Rommelspacher,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • Lutz G. Schmidt,

    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • El-Wui Loh

    Corresponding author
    1. Departments of Psychiatry (J.S., G.W., L.G.S., T.S.) and Clinical Neurobiology (J.S., H.R.), University Hospital Benjamin Franklin, Free University of Berlin, Berlin. Germany: the Department of Neurology (T.S.), University Hospital Charité. Campus Virchow Clinic, Humboldt University of Berlin, Berlin. Germany: the Social, Genetic, and Developmental Psychiatry Research Centre (D.B., J.P., E.-W.L.) and the Department of Psychological Medicine, Institute of Psychiatry (R.M., E.-W.L.), De Crespigny Park, Denmark Hill, London, United Kingdom; and the Department of Psychiatry (J.S.), Pomeranian Medical Academy, Szczecin, Poland.
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  • This study was supported by the Peacock Foundation, the Psychiatry Research Trust, the Deutsche Forschungsgemeinschaft (He 916/7-2), and an Alexander von Humboldt Stiftung Fellowship (to J.S.).

Reprints requests: El-Wui Loh, B.SC., Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom: Fax: 44 171 919-3407; E-mail: sphaewl@iop.bpmf.ac.uk

Abstract

Quantitative trait analyses in mice suggest a vulnerability locus for physiological alcohol withdrawal severity on a chromosomal segment that harbors the genes encoding the α1, α6, β2, and γ2 subunits of the γ2-aminobutyric acid type-A receptor (GABR). We tested whether genetic variation at the human GABAAα6, β2, and γ2 gene cluster on chromosome 5q33 confers vulnerability to alcohol dependence. The genotypes of three nucleotide substitution polymorphisms of the GABRA6, GABRB2, and GABRG2 genes were assessed in 349 German alcohol-dependent subjects and in 182 ethnically matched controls. To eliminate some of the genetic variance, three more homogeneous subgroups of alcoholics were formed by: (1) a history of alcohol withdrawal seizure or delirium (n= 106); (2) a history of parental alcoholism (n= 120); and (3) a comorbidity of dissocial personality disorder (n= 57). We found no evidence that any of the investigated allelic variants confers vulnerability to either alcohol dependence or severe physiological alcohol withdrawal symptoms or familial alcoholism (p > 0.05). The frequency of the T allele of the GABRA6 polymorphism was significantly increased in dissocial alcoholics [f(T) = 0.799] compared with the controls [f(T) = 0.658; p = 0.002; OR(T+) = 7.26]. Taking into account the high a priori risk of false-positive association findings due to multiple testing, further replication studies are necessary to examine the tentative phenotype-genotype relationship of GABRA6 gene variants and dissocial alcoholism.

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