Background: 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 7,800 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, traits in causal relationship with alcohol consumption as mediators, and various diseases as outcome. Results: Of 45 traits in association with alcohol consumption, 20 were in causal relationship with alcohol consumption. Gamma glutamyltransferase (GGT; β=9.44; CI,5.94-12.93; Pfdr=9.04×10-7), mean sphered cell volume (β=0.189; CI,0.11-0.27; Pfdr=1.00×10-4), mean corpuscular volume (β=0.271; CI,0.19-0.35; Pfdr=7.09×10-10) and mean corpuscular haemoglobin (β=0.278; CI,0.19-0.36; Pfdr=1.60×10-6) showed the strongest causal relationships. We also identified GGT and physical activity as mediators causing liver cirrhosis and alcohol dependence. Conclusion: Our study provides evidence of causality between alcohol consumption and 20 traits and a mediation effect for physical activity on health consequences of alcohol consumption.

Abstract Background: Alcohol consumption is linked to urinary sodium excretion and both of these traits are linked to hypertension and cardiovascular diseases (CVDs). The interplay between alcohol consumption and sodium on hypertension, and cardiovascular diseases (CVDs) is not well-described. Here, we used genetically predicted alcohol consumption and explored relationships between alcohol consumption, urinary sodium, hypertension, and CVDs. Methods: We performed a comparative analysis among 295,189 participants from the prospective cohort of the UK Biobank (baseline data collected between 2006 and 2010). We created a genetic risk score (GRS) using 105 published genetic variants in Europeans that were associated with alcohol consumption. We explored relationships between GRS, alcohol consumption, urinary sodium, blood pressure traits, and incident CVD. We used linear, logistic regression and Cox proportional hazards (PH) models in our analysis. Results: Our analyses supported an interaction effect between alcohol GRS and urinary sodium on hypertension (P interaction =0.03) and CVD (P interaction =0.03). In presence of high urinary sodium excretion, alcohol GRS increases blood pressure in a more enhanced fashion. Conclusions: Our results show that decrease in urinary sodium excretion offsets the risk posed by genetic risk of alcohol consumption.