Molecular Alterations Caused by Alcohol Consumption in the UK Biobank: A Mendelian Randomisation Study

Alcohol consumption is associated with the development of cardiovascular diseases, cancer, and liver disease. The biological mechanisms are still largely unclear. Here, we aimed to use an agnostic approach to identify phenotypes mediating the effect of alcohol on various diseases. Methods: We performed an agnostic association analysis between alcohol consumption (red and white wine, beer/cider, fortified wine, and spirits) with over 7800 phenotypes from the UK biobank comprising 223,728 participants. We performed Mendelian randomisation analysis to infer causality. We additionally performed a Phenome-wide association analysis and a mediation analysis between alcohol consumption as exposure, phenotypes in a causal relationship with alcohol consumption as mediators, and various diseases as the outcome. Results: Of 45 phenotypes in association with alcohol consumption, 20 were in a causal relationship with alcohol consumption. Gamma glutamyltransferase (GGT; beta = 9.44; 95% CI = 5.94, 12.93; P-fdr = 9.04 x 10(-7)), mean sphered cell volume (beta = 0.189; 95% CI = 0.11, 0.27; P-fdr = 1.00 x 10(-4)), mean corpuscular volume (beta = 0.271; 95% CI = 0.19, 0.35; P-fdr = 7.09 x 10(-10)) and mean corpuscular haemoglobin (beta = 0.278; 95% CI = 0.19, 0.36; P-fdr = 1.60 x 10(-6)) demonstrated the strongest causal relationships. We also identified GGT and physical inactivity as mediators in the pathway between alcohol consumption, liver cirrhosis and alcohol dependence. Conclusion: Our study provides evidence of causality between alcohol consumption and 20 phenotypes and a mediation effect for physical activity on health consequences of alcohol consumption.