Variation in adiposity is associated with cardiometabolic disease outcomes, but the mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of adiposity, proxied by body mass index (BMI), on 3,622 unique plasma proteins measured by the SomaLogic platform in 2,737 healthy participants from the INTERVAL study of UK blood donors. We conducted both observational and Mendelian randomization analyses where we used a genetic risk score for BMI as an instrument to estimate effects of BMI on protein levels. Our results suggest that BMI has a broad impact on the human plasma proteome, with estimated effects of BMI appearing strongest on proteins including circulating leptin, sex hormone-binding globulin and fatty acid-binding protein-4. We also provide evidence that proteins most altered by BMI are enriched for genes involved in cardiovascular disease. Altogether, these results help to focus attention onto new potential proteomic signatures of obesity-related disease.

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