Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis.
Holmes, Michael V;
Lange, Leslie A;
Palmer, Tom;
Lanktree, Matthew B;
North, Kari E;
Almoguera, Berta;
Buxbaum, Sarah;
Chandrupatla, Hareesh R;
Elbers, Clara C;
Guo, Yiran;
+24 more...Hoogeveen, Ron C;
Li, Jin;
Li, Yun R;
Swerdlow, Daniel I;
Cushman, Mary;
Price, Tom S;
Curtis, Sean P;
Fornage, Myriam;
Hakonarson, Hakon;
Patel, Sanjay R;
Redline, Susan;
Siscovick, David S;
Tsai, Michael Y;
Wilson, James G;
van der Schouw, Yvonne T;
FitzGerald, Garret A;
Hingorani, Aroon D;
Casas, Juan P;
de Bakker, Paul IW;
Rich, Stephen S;
Schadt, Eric E;
Asselbergs, Folkert W;
Reiner, Alex P;
Keating, Brendan J;
(2014)
Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis.
American journal of human genetics, 94 (2).
pp. 198-208.
ISSN 0002-9297
DOI: https://doi.org/10.1016/j.ajhg.2013.12.014
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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/m(2) 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/m(2) 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/m(2) 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.