Abstract P535: Associations of Genetically Determined Favourable and Unfavourable Adiposity Across the Phenome

Abstract

Background: The large-scale investigation of the genetic architecture of favourable adiposity (FA) and unfavourable adiposity (UFA) may unravel mechanisms coupling higher adiposity and cardiometabolic comorbidities, and may in turn aid in the prevention, prediction and management of these diseases. Aims and Objectives: We aimed to interrogate FA and UFA in relation to a plethora of clinical outcomes, investigate their causality, and test whether a healthy lifestyle interacts with FA/UFA for the risk of disease. Materials and Methods: We performed a Mendelian randomisation-phenome-wide association study (MR-PheWAS) to identify health outcomes associated with FA and UFA. We first conducted a PheWAS of FA and UFA with 988 phenotypes in 426,295 UK Biobank individuals. Health outcomes passing false-discovery rate (FDR) correction for multiple testing were taken forward to MR analyses. SNP-outcome associations were extracted from external GWAS consortia data. Finally, we examined the association between FA/UFA tertiles of genetic risk and tertiles of lifestyle score and incident health outcomes using proportional hazards models. Results: Our two sample MR results suggest that a 1-SD higher genetically instrumented FA is associated with lower odds of type 2 diabetes (OR: 0.05, 95% CI: 0.02 to 0.11), hypertension (0.30, 0.18 to 0.50) and coronary atherosclerosis (0.25, 0.10 to 0.62), and with higher odds of ventral hernia (18.15, 4.22-77.97). Moreover, 1-SD higher genetically determined UFA was associated with increased odds of type 2 diabetes (5.30, 3.27-8.61), hypertension (2.40, 1.55-3.71), myocardial infarction (1.99, 1.49-2.65), cholelithiasis (2.92, 1.87-4.56), and atrial fibrillation (2.17, 1.28-3.69) at significance passing FDR q<0.05. Sensitivity analyses were consistent with the main results. Our Cox regression model indicated that a favourable lifestyle is associated with a more pronounced risk reduction in cardiometabolic health outcomes and can have a more substantial impact on cardiometabolic and inflammatory conditions for individuals with either a high FA and a low UFA GRS profiles. Conclusions: Our findings offer novel insight into previously unreported effects of favourable and unfavourable adiposity, suggesting that a healthy lifestyle can benefit individuals with both favourable and unfavourable genetic risk scores. This highlights the importance of population-wide lifestyle approaches to address the problem of obesity and risk-stratifying the population according to favourable and unfavourable adiposity.