Background Body mass index (BMI) and alcohol consumption are suggested to independently and interactively increase the risk of liver disease. We assessed this combined effect using factorial Mendelian randomization (MR). Methods We used multivariable adjusted regression and MR to estimate individual and joint associations of BMI and alcohol consumption and liver disease biomarkers (alanine aminotransferase (ALT) γ-glutamyltransferase (GGT)) and incident liver disease. We undertook a factorial MR study splitting participants by median of measured BMI or BMI allele score then by median of reported alcohol consumption or ADH1B genotype (AA/AG and GG), giving four groups; low BMI/low alcohol (−BMI/−alc), low BMI/high alcohol (−BMI/+alc), high BMI/low alcohol (+BMI/−alc) and high BMI/high alcohol (+BMI/+alc). Results Individual positive associations of BMI and alcohol with ALT, GGT and incident liver disease were found. In the factorial MR analyses, considering the +BMI/+alc group as the reference, mean circulating ALT and GGT levels were lowest in the −BMI/−alc group (−2.32% (95% CI: −4.29, −0.35) and −3.56% (95% CI: −5.88, −1.24) for ALT and GGT respectively). Individuals with −BMI/+alc and +BMI/−alc had lower mean circulating ALT and GGT compared to the reference group (+BMI/+alc). For incident liver disease multivariable factorial analyses followed a similar pattern to those seen for the biomarkers, but little evidence of differences between MR factorial categories for odds of liver disease. Conclusions Consistent results from multivariable regression and MR analysis, provides compelling evidence for the individual adverse effects of BMI and alcohol consumption on liver disease. Intervening on both BMI and alcohol may improve the profiles of circulating liver biomarkers. However, this may not reduce clinical liver disease risk.

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