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.

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

“…This functional variant is negatively associated with drinking behaviors, mainly in European populations (Gelernter et al, 2014). We replicated prior findings.…”

“…PheWAS analyses are considered a useful post-GWAS approach; such analyses can deepen our understanding of the range of phenotypic effects associated with GWASidentified risk alleles (Bush et al, 2016). The risk alleles we studied are recognized has having large effects on nicotine response and alcohol metabolism (The Tobacco and Genetics Consortium, 2010; Gelernter et al, 2014;Quillen et al, 2014). Our results provide strong support for either pleiotropic or consequent, or both, effects of these risk alleles Figure 2 Phenotypic associations of ADH1B rs1229984 in transpopulation meta-analysis (META) and in African (AFR), Asian (ASN), European (EUR), and Hispanic (HISP) samples.…”

“…An additional sample of 2379 EUR subjects was used to replicate the findings of ADH1B rs1229984 (because this variant generated the most relevant results in the PheWAS conducted). Detailed information about phenotyping and genotyping procedures for the replication cohort are described in our previous GWAS of alcohol-and substance-dependence traits (Gelernter et al, 2014;Gelernter et al, 2015).…”

“…We chose these variants on the basis of numerous GWAS (Gelernter et al, 2014;Xu et al, 2015) and candidate-locus studies (Sherva et al, 2010;Hart et al, 2015;Jensen et al, 2015), and a recent meta-analysis of genetic studies of nicotine and alcohol traits (Buhler et al, 2015) and GWAS performed previously in different population groups (David et al, 2012;Gelernter et al, 2014).…”

“…Numerous genetic studies, including genome-wide association studies (GWAS), have examined smoking and drinking behaviors, and certain risk/protective alleles have been identified and validated (The Tobacco and Genetics Consortium, 2010;Gelernter et al, 2014;Gelernter et al, 2015;Buhler et al, 2015). The best replicated loci for drinking behaviors map to genes encoding alcohol-metabolizing enzymes.…”