Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study
Open accessAbstract
Importance: Higher body mass index (BMI) is a risk factor for cardiometabolic disease; however, the underlying causal associations remain unclear. Objectives: To use UK Biobank data to report causal estimates of the association between BMI and cardiometabolic disease outcomes and traits, such as pulse rate, using mendelian randomization. Design, Setting, and Participants: Cross-sectional baseline data from a population-based cohort study including 119 859 UK Biobank participants with complete phenotypic (medical and sociodemographic) and genetic data. Participants attended 1 of 22 assessment centers across the United Kingdom between 2006 and 2010. The present study was conducted from May 1 to July 11, 2016. Main Outcomes and Measures: Prevalence of hypertension, coronary heart disease, and type 2 diabetes were determined at assessment, based on self-report. Blood pressure was measured clinically. Participants self-reported sociodemographic information pertaining to relevant confounders. A polygenic risk score comprising 93 single-nucleotide polymorphisms associated with BMI from previous genome-wide association studies was constructed, and the genetic risk score was applied to derive causal estimates using a mendelian randomization approach. Results: Of the 119 859 individuals included in the study, 56 816 (47.4%) were men; mean (SD) age was 56.87 (7.93) years. Mendelian randomization analysis showed significant positive associations between genetically instrumented higher BMI and risk of hypertension (odds ratio [OR] per 1-SD higher BMI, 1.64; 95% CI, 1.48-1.83; P = 1.1 × 10-19), coronary heart disease (OR, 1.35; 95% CI, 1.09-1.69; P = .007) and type 2 diabetes (OR, 2.53; 95% CI, 2.04-3.13; P = 1.5 × 10-17), as well as systolic blood pressure (β = 1.65 mm Hg; 95% CI, 0.78-2.52 mm Hg; P = 2.0 × 10-04) and diastolic blood pressure (β = 1.37 mm Hg; 95% CI, 0.88-1.85 mm Hg; P = 3.6 × 10-08). These associations were independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history. Conclusions and Relevance: The results of this study add to the burgeoning evidence of an association between higher BMI and increased risk of cardiometabolic diseases. This finding has relevance for public health policies in many countries with increasing obesity levels.
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MR is being widely applied to quantitative traits with the aim of discovering modifiable risk factors for disease that are causal and amenable to therapeutic modification.
“With increasing availability of large-scale phenotyping (and genotyping), MR is being widely applied to quantitative traits (e.g. markers or adiposity, such as body mass index 13-16 ; blood lipids such as HDL-cholesterol 17-19 ; inflammation-related proteins such as interleukin-6 receptor 20,21 12 ) with the aim of discovering modifiable risk factors for disease that are causal and amenable to the”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [16]
Adiposity increases systolic blood pressure, which mediates part of the effect of BMI on risk of coronary artery disease.
“A further example is the causal role that adiposity plays in CHD: adiposity increases systolic blood pressure 13,16 which mediates part of the effect of BMI on risk of CAD 55 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [16]
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- Authors
- Lyall, D. M., Celis-Morales, C., Ward, J., Iliodromiti, S., Anderson, J. J., Gill, J. M. R., Smith, D. J., Ntuk, U. E., Mackay, D. F., Holmes, M. V., Sattar, N., & Pell, J. P.
- Affiliations
- University of Glasgow (GB)
- Institute of Health & Wellbeing, University of Glasgow, Glasgow, Scotland
- National Institute for Health and Care Research (GB)
- Corresponding author
- Lyall, Donald M.
- ORCID
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2017-08-01
- Volume
- 2
- Issue
- 8
- Pages
- 882
- ISSN
- 2380-6583 (ISSN-L)
- PMC
- PMC5710596
- OpenAlex
- W2730419426
- Cited by
- 235
- References
- 29
- Citations by year
- 2026: 9 · 2025: 25 · 2024: 27 · 2023: 24 · 2022: 36 · 2021: 27 · 2020: 28 · 2019: 26 · 2018: 23 · 2017: 9
- FWCI
- 15.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Cardiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council (MR/N015177/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Keywords
- body mass index, cardiometabolic disease, hypertension, coronary artery disease, type 2 diabetes, systolic blood pressure, diastolic blood pressure, pulse rate, polygenic risk score, Mendelian randomization, causal inference, obesity, UK Biobank, single nucleotide polymorphisms, cardiovascular risk factors, pulse wave analysis, heart rate variability
- MeSH terms
- Alcohol Drinking, Blood Pressure, Coronary Disease, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, United Kingdom, Heart Rate, Humans, Hypertension, Male, Middle Aged, Obesity, Smoking, Social Class, Cohort Studies, Body Mass Index, Prevalence, Odds Ratio, Biological Specimen Banks, Genetic Predisposition to Disease, Multifactorial Inheritance, Stroke, Polymorphism, Single Nucleotide, Overweight, Genome-Wide Association Study, Mendelian Randomization Analysis
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