Diet and lifestyle-related obesogenic environmental factors influence type 2 diabetes (T2D) risk, but there is little evidence that gene-environment (GxE) interactions underlie T2D susceptibility. We investigated whether obesogenic environmental factors (which, of course, are themselves partly genetic) interact with T2D-associated genetic variants to accentuate T2D risk using 375,736 unrelated European subjects from UK Biobank (16,430 T2D cases, 359,306 controls). We captured individual genetic risk of T2D with a weighted genetic risk score (T2D-GRS) based on 403 established T2D-associated variants from European-ancestry GWAS. We also constructed six distinct partitioned GRSs by classifying T2D-associated variants based on their likely pathophysiological mechanism (related to e.g., adiposity (T2D-GRSadiposity), beta-cell function, insulin action, mixed features). A logistic regression model was fitted to test for interactions between each GRS and environmental factor (duration and frequency of moderate/vigorous physical activity, sedentary lifestyle, MET, alcohol intake, dietary fat content, Townsend deprivation index (TDI), daytime nap and depression) on T2D, adjusted for age, sex, genotyping array and ethnic background (10 principal components). There was no evidence of statistically-significant interaction between any of the environmental factors and either the combined or partitioned T2D-GRS (p>0.0006, Bonferroni for 77 independent tests). There was suggestive interaction between frequency of alcohol intake and T2D-GRSadiposity on T2D risk (betainteraction=0.08 [95% CI=0.02-0.14]; pinteraction=0.008). These findings stand in contrast with strong interactions between the same environmental factors and T2D-GRSadiposity when using BMI as the outcome (e.g., for TDI, pinteraction=10-17). Our study finds little evidence of substantial interaction between individual T2D genetic risk profiles and obesogenic environmental factors with respect to T2D as the outcome.
A. Nag: None. A. Mahajan: None. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck & Co., Inc. Consultant; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited.
