Identification of gene-environment interactions and causal pathways for obesogenic cardiometabolic diseases

The public health impact of the study is that obesity is a serious health epidemic world-wide. Obesity predisposes to coronary heart disease (CHD), type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and high serum lipid levels. Deciphering gene-environment interactions (GxEs) underlying obesity will help identify factors contributing to its increasing prevalence and development of these concomitant cardiometabolic disorders. We have planned GxE analyses in the UK Biobank data for the DNA variants that we have previously shown to respond to environmental changes and alter expression in human adipose tissue and liver. We aim to test this limited set of DNA variants for GxEs and combined obesity-dependent effects on CHD, T2D, NAFLD, and high serum lipid levels. We also aim to perform causality analysis using cardiometabolic genome-wide association study (GWAS) variants and traits to identify causal pathways for CHD, T2D, and NAFLD. Our scientific rationale is that by improving the understanding of the genetic variants that mediate responses to an environment, we can elucidate the unknown gene-environment interactions underlying the increasing prevalence of obesity, disentangle detrimental lifestyle choices from genetic risk factors, and identify obese individuals with the highest risk to develop cardiometabolic disorders. It is also important to identify causal pathways for disease outcomes. The estimated duration of the project is 3 years. The proposed research meets the purpose of the UK Biobank to improve the prevention, diagnosis and treatment of illnesses.