Causal association BMI and cardio-metabolic disease confirmed by genetic studies

14-7-2017 • Lyall DM, et al, JAMA Cardiol 2017

Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank

A Mendelian Randomization Study

Lyall DM, Celis-Morales C, Ward J, et al.
JAMA Cardiology 2017; published online ahead of print

Introduction and Methods

Correlations between high BMI and cardiometabolic disease risk usually arise from observational studies. However, these studies are unable to fully account for confounding by shared risk factors, which, in contrast, can be achieved by mendelian randomization studies.
Studies comparing observational with mendelian randomization estimates of the association between BMI and coronary heart disease (CHD), stroke and type 2 diabetes mellitus (T2DM), reported discrepant ORs and showed inconsistency in terms of finding significant associations with CHD and stroke [1-3].
In this study, 119,859 usable data of the UK Biobank with was used to explore whether a true association exists between BMI and cardio-metabolic diseases in a large cohort with detailed measurements of covariates and, if so, whether BMI has a causal relationship with other health-related phenotypes.
For this, all participants completed physical, sociodemographic and medical assessments from 2006 to 2010. Non-white Europeans, participants with a relatedness coefficient >0.0442 (e.g. first cousins), cases with mismatch between reported and genetic gender or with failure at the UK Biobank quality controlling as well as individuals without genetic data, were excluded from the analysis.
A 93 single-nucleotide polymorphism (SNP) polygenic risk (PGR) score based on a genome-wide association study with 97 BMI-related loci of 339,224 individuals, including 56 newly discovered SNPs, was used [4]. Conventional mendelian randomization as well as the mendelian randomization (MR)-Egger method was used [5].

Main results

  • In the fully adjusted models of the observational analyses, an SD increase in BMI (4.83 kg/m2) was associated with risk of stroke (OR 1.26, 95% CI 1.21-1.31, P=2.0*10−29), CHD (OR 1.43, 95% CI 1.40-1.46, P=2.0*10−184), type 2 diabetes (OR 1.97, 95% CI 1.93-2.02, P <4.51*10−308), hypertension (OR 1.75, 95% CI 1.73-1.78, P <4.51*10−308), higher SBP (β=3.02 mmHg, 95% CI 2.91-3.13 mmHg, P <4.5*10−308), higher DBP (β=2.82 mmHg, 95% CI 2.76-2.89 mmHg, P <4.5*10−308) and higher pulse rate (β=1.86 beats/min, 95% CI 1.79-1.94 beats/min, P <4.5*10−308).
  • The conventional mendelian randomization analyses using individual participant data showed generally similar effect sizes compared with the observational analyses for hypertension (OR 1.64, 95% CI 1.48-1.83, P=1.1*10−19) and CHD (OR 1.35, 95% CI 1.09-1.69, P=0.007). On the other hand, the association with T2DM increased in magnitude compared to the observational OR (mendelian OR 2.53, 95% CI 2.04-3.13). There was no association between BMI and stroke (P=0.93).
  • Using MR-Egger, analyses did not identify evidence of unbalanced horizontal pleiotropy. Furthermore, the associations with SBP and DBP remained significant, but pulse rate did not. And results were similar in the partially vs fully adjusted models.
  • All findings remained unchanged for T2DM, CHD and hypertension, after removing participants who reported their age at diagnosis as unknown, chose not to answer or had an age ≤10 years at diagnosis as well as after including physical activity in the final models.


In a large population-based cohort study, BMI was associated with risk of hypertension, CHD, T2DM, elevated SBP and DBP based on causal mendelian randomization estimates, but not with stroke or pulse rate. These findings confirm that BMI represents an important modifiable risk factor for decreasing the risk of cardio-metabolic diseases in the general population.
Find this article online at JAMA cardiol


1. Nordestgaard BG, Palmer TM, Benn M, et al. The effect of elevated body mass index on ischemic heart disease risk: causal estimates from a mendelian randomisation approach. PLoS Med. 2012;9(5):e1001212.
2. HolmesMV, Lange LA, Palmer T, et al. Causal effects of body mass index on cardiometabolic traits and events: a mendelian randomization analysis. Am J Hum Genet. 2014;94(2):198-208.
3. Hagg S, Fall T, Ploner A, et al; European Network for Genetic and Genomic Epidemiology Consortium. Adiposity as a cause of cardiovascular disease: a mendelian randomization study. Int J Epidemiol. 2015;44(2):578-586.
4. Locke AE, Kahali B, Berndt SI, et al; LifeLines Cohort Study; ADIPOGen Consortium; AGEN-BMI
Working Group; CARDIOGRAMplusC4D Consortium; CKDGen Consortium; GLGC; ICBP; MAGIC Investigators; MuTHER Consortium; MIGen Consortium; PAGE Consortium; ReproGen Consortium; GENIE Consortium; International Endogene Consortium. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197-206.
5. Palmer TM, Sterne JAC, Harbord RM, et al. Instrumental variable estimation of causal risk ratios and causal odds ratios in mendelian randomization analyses. Am J Epidemiol. 2011;173 (12):1392-1403.


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