Genetic evidence for different adiposity phenotypes and their opposing influence on ectopic fat and risk of cardiometabolic disease.

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants, one with 'adverse' metabolic effects (UFA) and the other with, paradoxically, 'favourable' metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, higher fat in subcutaneous and visceral adipose tissue, liver and pancreas for UFA; and a favourable metabolic profile, lower risk of disease, higher CRP, higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for risk-increasing effect of UFA and protective effect of FA on type 2 diabetes, heart disease, hypertension, stroke, non-alcoholic fatty liver disease and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat, and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting and treating of cardiometabolic diseases.