Life‐course adiposity and severe liver disease: a Mendelian randomization analysis

Abstract Objective There is little evidence on the genetic associations between life‐course adiposity (including birth weight, childhood BMI, and adulthood BMI) and severe liver disease (SLD; including cirrhosis and liver cancer). The current study aimed to examine and contrast these associations. Methods Genetic variants were obtained from genome‐wide association studies. Two‐sample Mendelian randomization (MR) analyses were performed to assess the genetic associations of life‐course adiposity with SLD and liver biomarkers. Cox regression was used to estimate adjusted hazard ratios for SLD associated with genetic risk scores of life‐course adiposity and adulthood weight change in the China Kadoorie Biobank. Results In observational analyses, genetic predispositions to childhood adiposity and adulthood adiposity were each associated with SLD. There was a U‐shaped association between adulthood weight change and risk of SLD. In meta‐analyses of MR results, genetically predicted 1‐standard deviation increase in birth weight was inversely associated with SLD at a marginal significance (odds ratio: 0.81 [95% CI: 0.65–1.00]), whereas genetically predicted 1‐standard deviation higher childhood BMI and adulthood BMI were positively associated with SLD (odds ratio: 1.27 [95% CI: 1.05–1.55] and 1.79 [95% CI: 1.59–2.01], respectively). The results of liver biomarkers mirrored those of SLD. Conclusions The current study provided genetic evidence on the associations between life‐course adiposity and SLD.