Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117)

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.

Figure 1

Manhattan plot of genome-wide association study (GWAS) of alcohol consumption in UK Biobank (UKB; N=112 177). Red line indicates threshold for genome-wide significance (P⩽5 × 10⁻⁸) and the blue line for suggestive significance (P⩽5 × 10⁻⁶).

Figure 2

Linkage disequilibrium (LD) zoom plots of 2 common single-nucleotide polymorphisms (SNPs; minor allele frequency (MAF) >5%) most significantly associated (P<5 × 10⁻⁸) with alcohol consumption in UK Biobank. (a) The rs2872821 on chromosome 4 in KLB and (b) rs1260326 on chromosome 2 located in GKCR (http://locuszoom.sph.umich.edu/).

Figure 3

Genetic correlation between Alcohol Consumption in UK Biobank (UKB) and other traits using linkage disequilibrium (LD) score regression implemented in LD Hub. All traits presented pass false discovery rate (FDR) correction for multiple testing. HDL, high-density lipoprotein.