A sex-specific Mendelian randomization-phenome-wide association study of body mass index

Background: Trials of incretins are making it increasingly clear that body mass index (BMI) is linked to several diseases throughout life, but trials cannot easily provide a comprehensive assessment of the role of BMI in health-related attributes for men and women. To systematically investigate the role of BMI, we conducted a sex-specific Mendelian randomization-phenome-wide association study. Methods: We comprehensively examined the associations of genetically predicted BMI in women ( n : 194,174) and men ( n : 167,020) using health-related attributes from the UK Biobank with inverse variance weighting and sensitivity analysis. Results: BMI impacted 232 of 776 traits considered in women and 203 of 680 traits in men, after adjusting for false discovery; differences by sex were found for 105 traits, and 46 traits remained after adjusting for false discovery. BMI was more strongly positively associated with myocardial infarction, major coronary heart disease events, ischemic heart disease, and heart attack in men than women. BMI was more strongly positively associated with apolipoprotein B (ApoB) and diastolic blood pressure in women than men. Conclusions: Our study revealed that BMI might affect a wide range of health-related attributes and also highlights notable sex differences in its impact, including opposite associations for certain attributes, such as ApoB; and stronger effects in men, such as for cardiovascular diseases. Our findings underscore the need for nuanced, sex-specific policy related to BMI to address inequities in health. Funding: None.