Genome-wide association study of alcohol dependence implicates a region on chromosome 11

Howard J. Edenberg, Daniel L. Koller, Xiaoling Xuei, Leah Wetherill, Jeanette N. McClintick, Laura Almasy, Laura J. Bierut, Kathleen K. Bucholz, Alison Goate, Fazil Aliev, Danielle Dick, Victor Hesselbrock, Anthony Hinrichs, John Kramer, Sam Kuperman, John I. Nurnberger, John P. Rice, Marc A. Schuckit, Robert Taylor, B. Todd WebbJay A. Tischfield, Bernice Porjesz, Tatiana Foroud

    Research output: Contribution to journalArticlepeer-review

    235 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)840-852
    Number of pages13
    JournalAlcoholism: Clinical and Experimental Research
    Volume34
    Issue number5
    DOIs
    StatePublished - May 2010

    Keywords

    • Alcohol Dependence
    • Case-Control Study
    • Family Study
    • Gene Expression
    • Genome-Wide Association Study

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Toxicology
    • Psychiatry and Mental health

    Fingerprint Dive into the research topics of 'Genome-wide association study of alcohol dependence implicates a region on chromosome 11'. Together they form a unique fingerprint.

    Cite this