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

By Jonathan Allen Sulc, Anthony Sonrel, Ninon Mounier, Chiara Auwerx, Eirini Marouli, Liza Darrous, Bogdan Draganski, Tuomas O Kilpeläinen, Peter Joshi, Ruth J.F. Loos, Zoltán 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. As its genetic determinants have become increasingly elucidated, it has become feasible to investigate its health consequences via Mendelian randomisation (MR). To study the impact of different aspects of body morphology on health outcomes, we gathered fourteen body morphology measures and associated GWAS summary statistics from UK Biobank and used principal component analysis to reveal four major independent axes 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 signalling, whereas body fat distribution and lean mass are dependent on genes involved in morphogenesis and energy homeostasis. Using MR, we found that the adiposity component had the strongest impact on cardiometabolic health and obesity-related diseases and its genetic basis was intertwined with aspects of lower socio-economic status (SES). Overall body size affected many of the same diseases in an independent manner, but was linked to a more sedentary lifestyle with no change in SES. 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 more specifically linked to lipotoxicity, such as diabetes and heart disease. 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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