Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci

J. Gelernter, H. R. Kranzler, R. Sherva, L. Almasy, R. Koesterer, A. H. Smith, R. Anton, U. W. Preuss, M. Ridinger, D. Rujescu, N. Wodarz, P. Zill, H. Zhao, L. A. Farrer

    Research output: Contribution to journalArticle

    229 Scopus citations

    Abstract

    We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 × 10 -31; AAs: Arg369Cys, P=6.33 × 10 -17) and ADH1C in AAs (Thr151Thr, P=4.94 × 10 -10), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 × 10 -11), PDLIM5 in EAs (P=2.01 × 10 -8), and METAP in AAs (P=3.35 × 10 -8). We also identified a novel GWS association (1.17 × 10 -10) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

    Original languageEnglish (US)
    Pages (from-to)41-49
    Number of pages9
    JournalMolecular Psychiatry
    Volume19
    Issue number1
    DOIs
    StatePublished - Jan 1 2014

    Keywords

    • Alcohol dependence
    • alcohol-metabolizing enzymes
    • complex traits
    • genome-wide association
    • population differences
    • population-specific alleles

    ASJC Scopus subject areas

    • Molecular Biology
    • Psychiatry and Mental health
    • Cellular and Molecular Neuroscience

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