Genome-Wide Association Study of Alcohol Dependence Implicates a Region on Chromosome 11

Authors

  • Howard J. Edenberg,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Daniel L. Koller,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Xiaoling Xuei,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Leah Wetherill,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Jeanette N. McClintick,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Laura Almasy,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Laura J. Bierut,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Kathleen K. Bucholz,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Alison Goate,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Fazil Aliev,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Danielle Dick,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Victor Hesselbrock,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Anthony Hinrichs,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • John Kramer,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Sam Kuperman,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • John I. Nurnberger Jr,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • John P. Rice,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Marc A. Schuckit,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Robert Taylor,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • B. Todd Webb,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Jay A. Tischfield,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Bernice Porjesz,

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author
  • Tatiana Foroud

    1. From the Departments of Biochemistry and Molecular Biology (HJE, XX, JNM); Medical and Molecular Genetics (HJE, DLK, LW, TF); Center for Medical Genomics (HJE, XX, JNM); Psychiatry, Indiana University School of Medicine (JIN, TF), Indianapolis, Indiana; Southwest Foundation (LA), San Antonio, Texas; Washington University School of Medicine (LJB, KKB, AG, AH, JPR), St Louis, Missouri; Virginia Commonwealth University (FA, DD, BTW), Richmond, Virginia; University of Connecticut (VH), Farmington, Connecticut; University of Iowa (JK, SK), Iowa City, Iowa; University of California (MAS), San Diego, California; Howard University (RT), Washington, District of Columbia; Rutgers University (JAT), Piscataway, New Jersey; and SUNY Downstate Medical Center (BP), Brooklyn, NewYork.
    Search for more papers by this author

Reprint requests: Howard J. Edenberg, PhD, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS4063, Indianapolis, Indiana 46202-5122; Fax: 317-274-4686; E-mail: edenberg@iupui.edu

Abstract

Background:  Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk.

Methods:  We carried out a genome-wide association study (GWAS) on a case–control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p ≤ 2.1 × 10−4) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells.

Results:  Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case–control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3.

Conclusions:  We have identified several promising associations that warrant further examination in independent samples.

Ancillary