Taller height and risk of coronary heart disease and cancer, a within-sibship Mendelian randomization study
Background: Taller people have lower risk of coronary heart disease but higher risk of many cancers. Mendelian randomization (MR) studies in unrelated individuals (population MR) have suggested that these relationships are potentially causal. However, population MR studies are sensitive to demography (population stratification, assortative mating) and familial (indirect genetic) effects.
Methods: In this study, we performed within-sibship MR analyses using 78,988 siblings, a design robust against demography and indirect genetic effects of parents. For comparison we also applied population MR and estimated associations with measured height.
Results: Within-sibship Mendelian randomization estimated that one SD taller height lowers odds of coronary heart disease by 14% (95% CI: 3% to 23%) but increases odds of cancer by 18% (95% CI: 3% to 34%), highly consistent with population MR and height-disease association estimates. There was some evidence that taller height reduces systolic blood pressure and LDL cholesterol, which may mediate some of the protective effect of taller height on coronary heart disease risk.
Conclusions: For the first time, we have demonstrated that purported effects of height on adulthood disease risk are unlikely to be explained by demographic or familial factors, and so likely reflect an individual-level causal effect. Disentangling the mechanisms via which height affects disease risk may improve understanding of the aetiologies of atherosclerosis and carcinogenesis.
Funding: This project was conducted by researchers at the MRC Integrative Epidemiology Unit [MC_UU_00011/1] and also supported by a Norwegian Research Council Grant number 295989.
We used individual level data from the UK Biobank and HUNT cohorts. Participants in these studies have consented to the use of their data in medical research and so these data are not publicly available. Data access can be applied for by qualified researchers.For access to UK Biobank individual level participant data, please send enquiries to email@example.com and see information on the UK Biobank website http://www.ukbiobank.ac.uk. UK Biobank access generally involves submitting project proposals which are evaluated by the study data access committee.Researchers associated with Norwegian research institutes can apply for the use of HUNT data and samples with approval by the Regional Committee for Medical and Health Research Ethics. HUNT data is governed by Norwegian law, therefore researchers from other countries may apply if collaborating with a Norwegian Principal Investigator. Detailed information on the data access procedure of HUNT can be found at https://www.ntnu.edu/hunt/data.Statistical code for population and within-sibship models used in the manuscript is available on GitHub https://github.com/LaurenceHowe/WithinSibshipModels/
Article and author information
Norwegian Research Council (295989)
- Neil Martin Davies
Medical Research Council (00011/1)
- George Davey Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: This research has been conducted using the UK Biobank Resource under Application Number 15825. UK Biobank has ethical approval from the North West Multi-centre Research Ethics Committee (MREC). All UK Biobank participants provided written informed consent. The use of HUNT data in this study was approved by the Regional Committee for Ethics in Medical Research, Central Norway (2017/2479). All HUNT study participants provided written informed consent.
- Edward D Janus, University of Melbourne, Australia
- Preprint posted: July 19, 2021 (view preprint)
- Received: August 11, 2021
- Accepted: March 9, 2022
- Accepted Manuscript published: March 18, 2022 (version 1)
- Version of Record published: March 24, 2022 (version 2)
© 2022, Howe et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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