Diet, Lifestyle Behaviours and Other Risk Factors Associated With Type 2 Diabetes Beyond Body Mass Index: A Mendelian Randomization Study

Our aim in this study was to identify promising targets for the prevention of type 2 diabetes in addition to weight loss. We conducted a Mendelian randomization (MR) study to investigate the body mass index (BMI)-independent associations of 16 risk factors, including diet, lifestyle behaviours and others, with type 2 diabetes.We selected genetic variants as instrumental variables for diet, sleep traits, smoking, physical activity, education and blood pressure (BP) from European-descent genome-wide association studies (GWASs). Summary statistics for type 2 diabetes were derived from a recent GWAS with 74,124 European cases and 824,006 European controls. The inverse-variance weighted MR method was used to assess the associations of the risk factors with type 2 diabetes, followed by validation of robustness using different MR methods in sensitivity analyses.Genetically predicted insomnia (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.06 to 1.15), smoking initiation (OR, 1.14; 95% CI, 1.06 to 1.21), educational level (OR, 0.69; 95% CI, 0.65 to 0.74), hypertension (OR, 6.50; 95% CI, 3.13 to 13.50), systolic BP (OR, 1.02; 95% CI, 1.02 to 1.03) and diastolic BP (OR, 1.03; 95% CI, 1.02 to 1.03) had BMI-independent effects on type 2 diabetes risk. In addition, alcohol dependence (OR, 1.10; 95% CI, 1.05 to 1.16; BMI-adjusted OR, 1.04; 95% CI, 0.98 to 1.09) and vegetarian diet (OR, 0.50; 95% CI, 0.33 to 0.74; BMI-adjusted OR, 0.78; 95% CI, 0.57 to 1.06) appeared to be correlated with type 2 diabetes via a BMI-mediated pathway. Sensitivity analyses further confirmed the relationship between these factors and type 2 diabetes.In this systematic MR study, insomnia, smoking, education and BP had BMI-independent causal effects on the risk of type 2 diabetes, whereas alcohol dependence and vegetarian diet were associated with type 2 diabetes through BMI.