A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes

Obesity and type 2 diabetes are causally related, yet there is considerable

heterogeneity in the consequences of both conditions and the mechanisms

of action are poorly defined. Here we show a genetic-driven approach

defining two obesity profiles that convey highly concordant and discordant

diabetogenic effects. We annotate and then compare association signals

for these profiles across clinical and molecular phenotypic layers. Key

differences are identified in a wide range of traits, including cardiovascular

mortality, fat distribution, liver metabolism, blood pressure, specific lipid

fractions and blood levels of proteins involved in extracellular matrix

remodelling. We find marginal differences in abundance of Bacteroidetes

and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent

causal roles for waist-to-hip ratio, blood pressure and cholesterol content of

high-density lipoprotein particles in the development of diabetes in obesity.

We prioritize 17 genes from the discordant signature that convey protection

against type 2 diabetes in obesity, which may represent logical targets for

precision medicine approaches.