Sex-specific Mendelian randomization phenome-wide association study of basal metabolic rate

Observationally, higher basal metabolic rate (BMR) is associated with metabolism-related disorders, cancer, aging, and mortality. In this Mendelian randomization (MR) phenome-wide association study, using two-sample MR methods, we systematically and comprehensively investigated the health effects of genetically predicted BMR across the phenome sex-specifically. We obtained sex-specific genetic variants strongly (p < 5 × 10^{- 8}) and independently (r² < 0.001) predicting BMR from the UK Biobank and applied them to over 1,000 phenotypes within the same study. We combined genetic variant-specific Wald estimates using inverse-variance weighting, supplemented by sensitivity analysis. We used a false-discovery rate correction to allow for multiple comparisons as well as multivariable MR adjusted for body mass index and testosterone to investigate the independent effects of BMR on phenotypes with significant univariable associations. We obtained 217/219 genetic variants predicting BMR and applied them to 1,150/1,242 phenotypes in men/women, respectively. BMR was associated with 190/270 phenotypes in univariable analysis and 122/123 phenotypes in multivariable analysis in men/women. Examples of robust associations in multivariable analysis included those with neoplasms, diseases of the circulatory system, and growth and reproductive investment. In conclusion, BMR might affect a wide range of health-related outcomes. The underlying mechanisms and interactions between phenotypes warrant further study, as BMR is modifiable.