Taller height and risk of coronary heart disease and cancer: A within-sibship Mendelian randomization study

Laurence J Howe*, Ben Brumpton, Humaira Rasheed, Bjørn Olav Åsvold, George Davey Smith, Neil M Davies

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)
34 Downloads (Pure)

Abstract

Background: Taller people have a lower risk of coronary heart disease but a 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 MR estimated that 1 SD taller height lowers the odds of coronary heart disease by 14% (95% CI: 3-23%) but increases the odds of cancer by 18% (95% CI: 3-34%), highly consistent with population MR and height-disease association estimates. There was some evidence that taller height reduces systolic blood pressure and low-density lipoprotein cholesterol, which may mediate some of the protective effects of taller height on coronary heart disease risk.

Conclusions: For the first time, we have demonstrated that the 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 the understanding of the etiologies 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.

Original languageEnglish
Article numbere72984
Pages (from-to)1-15
JournaleLife
Volume11
DOIs
Publication statusPublished - 18 Mar 2022

Bibliographical note

Funding Information:
Quality Control filtering of the UK Biobank data was conducted by R Mitchell, G Hemani, T Dudding, and L Paternoster as described in the published protocol (https://doi.org/10.5523/bris.3074krb6t2fr j29yh2b03x3wxj). The University of Bristol support the MRC Integrative Epidemiology Unit (MC_ UU_00011/1). NMD was supported by a Norwegian Research Council grant number 295989. The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This publication is the work of the authors, who serve as the guarantors for the contents of this paper.

Funding Information:
Norwegian Research Council MRC Integrative Epidemiology Unit295989 Neil Martin Davies MC_UU_00011/1 Laurence J Howe Neil M Davies George Davey Smith The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Funding Information:
Background: Taller people have a lower risk of coronary heart disease but a 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 MR estimated that 1 SD taller height lowers the odds of coronary heart disease by 14% (95% CI: 3–23%) but increases the odds of cancer by 18% (95% CI: 3–34%), highly consistent with population MR and height-disease association estimates. There was some evidence that taller height reduces systolic blood pressure and low-density lipoprotein cholesterol, which may mediate some of the protective effects of taller height on coronary heart disease risk. Conclusions: For the first time, we have demonstrated that the 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 the understanding of the etiologies 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.

Publisher Copyright:
© Vaidžiulytė et al.

Structured keywords

  • Bristol Population Health Science Institute

Keywords

  • Adult
  • Body Height/genetics
  • Causality
  • Coronary Disease/epidemiology
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Neoplasms/epidemiology
  • Polymorphism, Single Nucleotide
  • Risk Factors

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