Abstract
Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10−23). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=−0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.
Highlights
In 2012, 5.9% of all global deaths were attributable to alcohol and roughly a quarter of all deaths in the 20–39-year-age group.[1]
Four of these loci are located among a cluster of alcohol metabolism genes on chromosome 4q23 (ADH1B/ADH1C and ADH5) and have been previously identified as risk loci for alcohol-related phenotypes.[9,12]
A single-nucleotide polymorphism (SNP) in KLB was associated with alcohol consumption and this locus has previously been identified in a large meta-analysis of alcohol consumption in Europeans.[15]
Summary
In 2012, 5.9% of all global deaths were attributable to alcohol and roughly a quarter of all deaths in the 20–39-year-age group.[1] Over 200 diseases are linked to alcohol consumption and the proportion of the global disease burden, measured in disabilityadjusted life years, is over 5%.1. Almost a quarter of disabilityadjusted life years attributable to alcohol consumption were the result of neuropsychiatric disorders such as alcohol use disorders (AUD) and major depressive disorder.[2]. There is a substantial genetic component to the variation in alcohol consumption, studies of alcohol use have largely focused on AUD to date. Using a sample of unrelated parents, the same authors estimated
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