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.

Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

“…Several two-sample MR studies have used summary association data from GWAS that have estimated the effect of genetic variants on the trait of interest conditioned on heritable covariables (e.g. (12)(13)(14)(15)(16)). The use of such GWAS data might have biased the findings of these MR studies for the reasons outlined above.…”

“…Despite the widespread use of covariable-adjusted summary associations (e.g. (12)(13)(14)(15)(16)), few considerations have been made about how this could affect the validity of results (e.g. (12-14, 17, 18)), particularly in the context of two-sample MR.…”

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

“…; Clarke et al . ). Further, FGF21 might exert a protective effect during sustained alcohol consumption, since FGF21‐KO mice exhibited more liver damage than WT mice after 16 weeks with 30% ethanol in their drinking water (Desai et al .…”

Genome‐wide association studies of alcohol dependence, DSM‐IV criterion count and individual criteria

“…49 Across these studies, the most robust association signal for rs1229984 appears to arise from Tolerance, which is notably an index of excessive consumption and consistent with the role of ADH1B in other studies of nonproblem alcohol intake. 50 Plausibly, the strong findings with Desire to cut drinking might also support this as epidemiological studies have shown this criterion to index liability to less severe AD (Table S2 and Figure S7), and therefore, serve as a marker of excessive drinking, rather than severe pathology and impairment. 10,[51][52][53] Differences in associations with other criteria could stem from the relative severity of individual criteria in each dataset or their relationship with excessive drinking.…”