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

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: body size, adiposity, predisposition to abdominal fat deposition, and lean mass. Mendelian randomization analysis showed that although body size and adiposity both contribute to the consequences of BMI, many of their effects are distinct, such as body size increasing the risk of cardiac arrhythmia (b = 0.06, p = 4.2 ∗ 10-17) while adiposity instead increased that 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 independent predicted effects significantly improved the prediction of obesity-related diseases (p < 10-10). The presented decomposition approach sheds light on the biological mechanisms underlying the heterogeneity of body morphology and its consequences on health and lifestyle.