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

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.

SUBMITTER: Gelernter J

PROVIDER: S-EPMC4165335 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

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

Molecular psychiatry 20131029 1

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 biologica ...[more]

PMID: 24166409

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Project description:BackgroundWe 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.MethodsOur 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.ResultsIn 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.ConclusionsThe key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.

Dataset Information

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

Publications

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

Similar Datasets

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