Causal relevance of obesity on the leading causes of death in women and men: A Mendelian randomization study

Abstract

AbstractBackgroundObesity 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 therefore tested associations of sex-specific genetic risk scores (GRSs) for body mass index (BMI), waist-hip-ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) with leading causes of mortality, using a Mendelian randomization (MR) framework.Methods and FindingsWe constructed sex-specific GRSs for BMI, WHR, and WHRadjBMI, including 565, 324, and 338 genetic variants, respectively. These GRSs were then used as instrumental variables to assess associations between the obesity traits and leading causes of mortality using an MR design in up to 422,414 participants from the UK Biobank. We also investigated associations with potential mediators and risk factors, including smoking, glycemic and blood pressure traits. Sex-differences were subsequently assessed by Cochran’s Q-test (Phet).Up to 227,717 women and 194,697 men with mean (standard deviation) age 56.6 (7.9) and 57.0 (8.1) years, body mass index 27.0 (5.1) and 27.9 (4.2) kg/m2and waist-hip-ratio 0.82 (0.07) and 0.94 (0.07), respectively, were included. Mendelian randomization analysis 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. A 1 standard deviation higher body mass index led to higher risk of type 2 diabetes in women (OR 3.81; 95% CI 3.42-4.25, P=8.9×10−130) than in men (OR 2.78; 95% CI 2.57-3.02, P=1.0×10−133, Phet=5.1×10−6). Waist-hip-ratio led to a higher risk of chronic obstructive pulmonary disease (Phet=5.5×10−6) and higher risk of chronic renal failure (Phet=1.3×10−4) in men than women.A limitation of MR studies is potential bias if the genetic variants are directly associated with confounders (pleiotropy), but sensitivity analyses such as MR-Egger supported the main findings. Our study was also limited to people of European descent and results may differ in people of other ancestries.ConclusionsObesity 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 implications on public health.