Get access

Role of GABRA2 in Moderating Subjective Responses to Alcohol

Authors

  • Sungwon Roh,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Sachio Matsushita,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Sachiko Hara,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Hitoshi Maesato,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Toshifumi Matsui,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Go Suzuki,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Tomohiro Miyakawa,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Vijay A. Ramchandani,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Ting-Kai Li,

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author
  • Susumu Higuchi

    1. From the Division of Clinical Research (SR, S Hara), Department of Psychiatry (SM, HM, GS, T Miyakawa, S Higuchi), and Department of Internal Medicine (T Matsui), National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan; Laboratory of Clinical and Translational Studies (VAR) and Office of the Director (TKL), National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
    Search for more papers by this author

  • Present address: Department of Mental Health Research, Seoul National Hospital (SR), Seoul, Korea; Department of Psychiatry, National Defense Medical College (GS), Saitama, Japan; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine (TKL), Durham, North Carolina.

Reprint requests: Susumu Higuchi, MD, PhD, Department of Psychiatry, National Hospital Organization Kurihama Alcoholism Center, 5-3-1 Nobi, Yokosuka, Kanagawa 239-0841, Japan; Fax: +81-46-849-7743; E-mail: h-susumu@db3.so-net.ne.jp

Abstract

Background:  Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the γ-aminobutyric acid A (GABAA) receptor α2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration.

Methods:  One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 ± 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis.

Results:  Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence–associated allele regardless of ALDH2 genotype.

Conclusions:  These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.

Ancillary