Keywords: body mass index; Mendelian randomization; Cardiometabolic
Authors: M. V. Holmes1,2, L. A. Lange3, T. Palmer4, M. B. Lanktree5, IBC BMI Mendelian Randomization Group, E. E. Schadt6, F. W. Asselbergs7,8,2, A. P. Reiner9,10, B. J. Keating1; 1University of Pennsylvania, Philadelphia, PA, United States, 2University College London, London, United Kingdom, 3University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, United States, 4University of Warwick, Warwick, United Kingdom, 5McMaster University, Hamilton, ON, Canada, 6Mount Sinai School of Medicine, New York, NY, United States, 7University Medical Center Utrecht, Utrecht, Netherlands, 8Durrer Center for Cardiogenetic Research, Utrecht, Netherlands, 9University of Virginia, Charlottesville, VA, United States, 10Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Abstract: Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses using 14 SNPs associated with BMI from a recent discovery analysis to investigate the causal role of BMI with cardiometabolic traits. We used eight population-based cohorts, including 34,538 individuals of European ancestry with 4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD) and 3,813 stroke cases. A genetically-elevated one kg/m2 increase in BMI resulted in higher levels of fasting glucose, insulin, interleukin-6 and systolic blood pressure but reduced levels of HDL-C and LDL-C (values reported in Table). Apart from LDL-C, all causal estimates were directionally concordant to observational estimates. A genetically-elevated one kg/m2 increase in BMI increased odds of T2D but did not affect risk of CHD or stroke. A meta-analysis incorporating published studies with 27,465 CHD events in 219,423 individuals yielded a pooled odds ratio of 1.04 (95%CI: 0.97, 1.12) per 1 kg/m2 increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits, however whether BMI causally impacts on CHD risk requires further evidence.