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Composite trait Mendelian Randomization reveals distinct metabolic and lifestyle consequences of differences in body shape

By Jonathan Sulc, Anthony Sonrel, Ninon Mounier, Chiara Auwerx, Eirini Marouli, Liza Darrous, Bogdan Draganski, Tuomas O. Kilpeläinen, Peter Joshi, Ruth J.F. Loos, Zoltan Kutalik

Posted 05 Sep 2020
medRxiv DOI: 10.1101/2020.09.03.20187567

Obesity is a major risk factor for a wide range of cardiometabolic diseases, however the impact of specific aspects of body morphology remains poorly understood. We combined the GWAS summary statistics of fourteen anthropometric traits from UK Biobank through principal component analysis to reveal four major independent axes summarizing 99% of genetically driven variation in body shape and size: overall body size, adiposity, predisposition to abdominal fat deposition, and lean mass. Enrichment analyses suggest that body size and adiposity are affected by genes involved in neuronal signaling, whereas body fat distribution and lean mass are dependent on genes involved in morphogenesis and energy homeostasis. Using Mendelian randomization, we found that although both body size and adiposity contribute to the consequences of BMI, many of their effects are distinct, such as body size increasing the risk of diseases of the veins (b [&ge;] 0.044, p [&le;] 8.9*10-10) and cardiac arrhythmia (b = 0.06, p = 4.2*10-17) while adiposity instead increased the risk of ischemic heart disease (b = 0.079, p = 8.2*10-21). The body mass-neutral component predisposing to abdominal fat deposition, likely reflecting a shift from subcutaneous to visceral fat, exhibited health effects that were weaker but specifically linked to lipotoxicity, such as ischemic heart disease (b = 0.067, p = 9.4*10-14) and diabetes (b = 0.082, p = 5.9*10-19). Combining their predicted effects significantly improved the prediction of obesity-related diseases, even when applied out-of-population (p < 10-10). The presented decomposition approach sheds light on the biological mechanisms underlying the remarkably heterogeneous nature of body morphology as well as its consequences on health and lifestyle.

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