Obesity traits are causally implicated with risk of cardiometabolic diseases. It remains unclear whether there are similar causal effects of obesity traits on other non-communicable diseases. Also, it is largely unexplored whether there are any sex-specific differences in the causal effects of obesity traits on cardiometabolic diseases and other leading causes of death.We constructed sex-specific genetic risk scores (GRS) for three obesity traits; body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI, including 565, 324, and 337 genetic variants, respectively. These GRSs were then used as instrumental variables to assess associations between the obesity traits and leading causes of mortality in the UK Biobank using Mendelian randomization. We also investigated associations with potential mediators, including smoking, glycemic and blood pressure traits. Sex-differences were subsequently assessed by Cochran’s Q-test (Phet).A Mendelian randomization analysis of 228,466 women and 195,041 men showed that obesity causes coronary artery disease, stroke (particularly ischemic), chronic obstructive pulmonary disease, lung cancer, type 2 and 1 diabetes mellitus, non-alcoholic fatty liver disease, chronic liver disease, and acute and chronic renal failure. Higher BMI led to higher risk of type 2 diabetes in women than in men (Phet=1.4×10-5). Waist-hip-ratio led to a higher risk of chronic obstructive pulmonary disease (Phet=3.7×10-6) and higher risk of chronic renal failure (Phet=1.0×10-4) in men than women.Obesity traits have an etiological role in the majority of the leading global causes of death. Sex differences exist in the effects of obesity traits on risk of type 2 diabetes, chronic obstructive pulmonary disease, and renal failure, which may have downstream implications for public health.Author summary Obesity is increasing globally and has been linked to major causes of death, such as diabetes and heart disease. Still, the causal effects of obesity on other leading causes of death is relatively unexplored. It is also unclear if any such effects differ between men and women.Mendelian randomization is a method that explores causal relationships between traits using genetic data. Using Mendelian randomization, we investigated the effects of obesity traits on leading causes of death and assessed if any such effects differ between men and women.We found that obesity increases the risks of heart disease, stroke, chronic obstructive pulmonary disease, lung cancer, diabetes, kidney disease, non-alcoholic fatty liver disease and chronic liver disease. Higher body mass index led to a higher risk of type 2 diabetes in women than in men, whereas a higher waist-hip ratio increased risks of chronic obstructive pulmonary disease and chronic kidney disease more in men than in women.In summary, obesity traits are causally involved in the majority of the leading causes of death, and some obesity traits affect disease risk differently in men and women. This has potential implications for public health strategies and indicates that sex-specific preventative measure may be needed.Abbreviations BMI, Body mass index; CAD: coronary artery disease; CLD, chronic liver disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; FG, fasting glucose; FI, fasting insulin; GIANT, Genetic Investigation of ANthropometric Traits; GRS, genetic risk score; GWAS, genomewide association study; MAGIC, the Meta-Analyses of Glucose and Insulin-related traits Consortium; MR, Mendelian randomization; NAFLD, non-alcoholic fatty liver disease; OR, odds ratio; T1D, type 1 diabetes; T2D, type 2 diabetes; SBP, systolic blood pressure; SD, standard deviation; SNP, single nucleotide polymorphism; WHO, the World Health Organization; WHR, waist-hip-ratio; WHRadjBMI, waist-hip-ratio adjusted for body mass index.

Causal relationships between obesity and the leading causes of death in women and men