Genome-wide association study of nicotine dependence in American populations: Identification of novel risk loci in both African-Americans and European-Americans

Joel Gelernter, Henry R. Kranzler, Richard Sherva, Laura Almasy, Aryeh I. Herman, Ryan Koesterer, Hongyu Zhao, Lindsay A. Farrer

    Research output: Contribution to journalArticle

    49 Scopus citations

    Abstract

    Background We report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the Fagerström Test for Nicotine Dependence in European-American (EA) and African-American (AA) populations. Methods Our sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project [via the database of Genotypes and Phenotypes (dbGAP)]. GWAS analysis considered Fagerström Test for Nicotine Dependence score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a single nucleotide polymorphism (SNP) subset. Results In EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 × 10-8 (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 × 10-10). Two chromosome 8 regions were associated: p = 4.45 × 10-8 at DLC1 SNP rs289519 (unadjusted) and p = 1.10 × 10-9 at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with nicotine dependence and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p = 1.46 × 10-7) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase and adenosine monophosphate-activated protein kinase pathways in EAs. Conclusions The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.

    Original languageEnglish (US)
    Pages (from-to)493-503
    Number of pages11
    JournalBiological Psychiatry
    Volume77
    Issue number5
    DOIs
    StatePublished - Mar 1 2015

    Keywords

    • AMPK pathway
    • DISC1
    • DLC1
    • FTND
    • GWAS
    • Nicotine dependence
    • Population differences
    • eNOS pathway

    ASJC Scopus subject areas

    • Biological Psychiatry

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