Causal effects of body mass index on cardiometabolic traits and events: A Mendelian randomization analysis

Michael V. Holmes, Leslie A. Lange, Tom Palmer, Matthew B. Lanktree, Kari E. North, Berta Almoguera, Sarah Buxbaum, Hareesh R. Chandrupatla, Clara C. Elbers, Yiran Guo, Ron C. Hoogeveen, Jin Li, Yun R. Li, Daniel I. Swerdlow, Mary Cushman, Tom S. Price, Sean P. Curtis, Myriam Fornage, Hakon Hakonarson, Sanjay R. PatelSusan Redline, David S. Siscovick, Michael Y. Tsai, James G. Wilson, Yvonne T. Van Der Schouw, Garret A. Fitzgerald, Aroon D. Hingorani, Juan P. Casas, Paul I W De Bakker, Stephen S. Rich, Eric E. Schadt, Folkert W. Asselbergs, Alex P. Reiner, Brendan J. Keating

Research output: Contribution to journalArticlepeer-review

166 Scopus citations


Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m2 genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m2 genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR 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 CHD risk requires further evidence.

Original languageEnglish (US)
Pages (from-to)198-208
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Feb 6 2014


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