Height is a classical complex trait influenced by genetic and early-life environmental factors. Despite the nonmodifiable nature of adult height, evaluating the effects of height on noncommunicable disease risk can give insights into the etiology of adulthood diseases (Emerging Risk Factors Collaboration, 2012; Davey Smith et al., 2000). Two major groupings of diseases, cardiovascular disease and cancer, have divergent associations with height (Emerging Risk Factors Collaboration, 2012; Davey Smith et al., 2000; Stefan et al., 2016). Taller people are less likely to develop cardiovascular disease, including coronary heart disease (CHD) (Emerging Risk Factors Collaboration, 2012; Nelson et al., 2015; Nüesch et al., 2016; Hebert et al., 1993; Batty et al., 2009; Marouli et al., 2019) and stroke (Njølstad et al., 1996), but more likely to be diagnosed with cancer (Emerging Risk Factors Collaboration, 2012; Green et al., 2011; Zhang et al., 2015; Thrift et al., 2015; Dixon-Suen et al., 2018; Batty et al., 2006; Gunnell et al., 2001; Perkins et al., 2016). The mechanisms via which height influences disease risks are unclear. The association between height and cardiovascular disease may be mediated via favorable lipid profiles (Emerging Risk Factors Collaboration, 2012; Nelson et al., 2015), lower systolic blood pressure (SBP) (Emerging Risk Factors Collaboration, 2012; Langenberg et al., 2003), lung function (Marouli et al., 2019; Gunnell et al., 2003), lower heart rate (Smulyan et al., 1998), and coronary artery vessel dimension (O’Connor et al., 1996). The increased cancer incidence among taller individuals could relate to early-life exposure to hormones such as insulin-like growth factor 1 (IGF-1) (Renehan et al., 2004; Clayton et al., 2011) or the increased number of cells in taller individuals (Stefan et al., 2016; Green et al., 2011; Albanes and Winick, 1988). However, although overall cancer risk is higher among taller individuals (Green et al., 2011; Batty et al., 2006; Gunnell et al., 2001), there is some evidence for heterogeneity across cancer subtypes with null or inverse associations observed between height and risk of stomach, oropharyngeal, and esophageal cancers (Green et al., 2011; Batty et al., 2006; Gunnell et al., 2001; Perkins et al., 2016).

Height is highly heritable, but the average height across the European populations has increased over the last hundred years (Hatton, 2013), illustrating the effects of early-life environmental factors such as nutrition and childhood infections. The associations of height with adulthood diseases and relevant biomarkers could reflect the biomechanical effects relating to increased stature (e.g., number of cells or larger arteries; O’Connor et al., 1996) or could reflect confounding by early-life environmental factors that influence both height and later-life health such as parental socioeconomic position. For example, wealthier parents may provide their offspring with better nutrition, leading to increased adult height, and a better education, potentially leading to improved health in adulthood (Perkins et al., 2016). Thus, it is unclear whether height has a causal effect on the risk of cardiovascular disease and cancer or if a confounding factor influences both height and disease risk.

Mendelian randomization (Smith and Ebrahim, 2003) analyses, using genetic variants associated with height as a proxy for observed height, have been used to strengthen the evidence for causal effects of height on adulthood diseases (Nelson et al., 2015; Nüesch et al., 2016; Zhang et al., 2015; Thrift et al., 2015; Dixon-Suen et al., 2018). The underlying premise being that genetic variants associated with height, unlike height itself, are unlikely to be associated with potential confounders such as childhood nutrition. However, there is growing evidence that estimates from genetic epidemiological studies using unrelated individuals may capture effects relating to demography (population stratification, assortative mating) and familial effects (e.g., indirect genetic effects of relatives where parental genotype influences offspring phenotypes) (Barton and Hermisson, 2019; Berg et al., 2019; Sohail et al., 2019; Ruby et al., 2018; Haworth et al., 2019; Brumpton et al., 2019; Lee et al., 2018; Kong et al., 2018; Young et al., 2018). Indeed, recent articles have illustrated the potential for genetic analyses of height to be affected by these biases (Berg et al., 2019; Sohail et al., 2019), including a Mendelian randomization study of height on education (Brumpton et al., 2019). One approach to overcome these potential biases is to use data from siblings (Brumpton et al., 2019; Davies et al., 2019) and exploit the shared early-life environment of siblings and the random segregation of alleles during meiosis (Smith and Ebrahim, 2003). Indeed, true Mendelian randomization was initially proposed as existing within a parent-offspring design (Smith and Ebrahim, 2003; Davey Smith et al., 2020; Figure 1).

Figure 1

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Here, we used data from 40,275 siblings from UK Biobank (Bycroft et al., 2018) and 38,723 siblings from the Norwegian HUNT study (Krokstad et al., 2013) to estimate the effects of adulthood height on CHD, cancer risk, and relevant biomarkers. Study-level information is contained in Table 1. We report the estimates of the effects of height on CHD and cancer from both phenotypic models and Mendelian randomization, with and without accounting for family structure.

In this study, we used sibling data from two large biobanks to estimate the effects of height on CHD, cancer, and relevant biomarkers. We found consistent evidence across all models, including within-sibship Mendelian randomization, that taller height is protective against CHD but increases the risk of cancers. We found less consistent evidence for the effects of height on biomarkers; population and within-sibship phenotypic models as well as population Mendelian randomization models suggested modest effects of taller height on SBP, LDL-C, and HDL-C. However, the confidence intervals for within-family Mendelian randomization of height and biomarkers were too wide to draw strong conclusions.

Our findings are largely consistent with previous studies (Emerging Risk Factors Collaboration, 2012; Nelson et al., 2015; Nüesch et al., 2016; Hebert et al., 1993; Marouli et al., 2019; Green et al., 2011; Zhang et al., 2015; Thrift et al., 2015; Dixon-Suen et al., 2018; Carslake et al., 2013) that used nonsibling designs, and with the hypothesis that height affects CHD and cancer risk. However, previous studies were potentially susceptible to bias relating to geographic and socioeconomic variation in height and height genetic variants (Barton and Hermisson, 2019; Sohail et al., 2019; Lee et al., 2018). Indeed, a recent within-sibship Mendelian randomization study found that the previously reported effects of height and body mass index on educational attainment were greatly attenuated when using siblings (Brumpton et al., 2019). Here, we provided robust evidence for individual-level effects of height by demonstrating that the previous evidence for effects of height on adulthood disease risk is unlikely to have been confounded by demography or indirect genetic effects. The major strengths of our work are the use of within-sibship Mendelian randomization (Davies et al., 2019) and the triangulation (Lawlor et al., 2016) of evidence from across phenotypic, genetic, and within-sibship models.

A limitation of our analyses is that because of limited sibling data and the statistical inefficiency of within-family models, we have limited statistical power to investigate the effects of height on disease subtypes,further explore the mechanisms using multivariable Mendelian randomization (Burgess and Thompson, 2015), and perform sensitivity analyses to evaluate horizontal pleiotropy. An additional limitation is that our study may have been susceptible to selection and survival biases relating to nonrandom participation in UK Biobank and/or HUNT and the requirement of at least two siblings to survive to be recruited. Indeed, cancer and CHD are both leading worldwide causes of mortality and so cases for one disease may have a reduced likelihood of developing the other disease due to increased mortality. Therefore, our study may have been susceptible to survival bias relating to competing risks. We mitigated this by defining cases for both diseases using both nonfatal and fatal events. Our study analyzed families with two or more siblings jointly participating in a cohort; nevertheless, further research is required to investigate the impact of selection bias on family studies.

Adulthood height is nonmodifiable, and the interpretation of causality is nuanced because it is unclear whether biological effects relate to stature itself, increased childhood growth, or to factors highly correlated with height such as lung function (Marouli et al., 2019; Gunnell et al., 2003) and artery length (Palmer et al., 1990). Previous studies Gunnell et al., 2001; Langenberg et al., 2003; Gunnell et al., 2003; Regnault et al., 2014 have explored the possibility that associations may relate to dimensions of height, with evidence that blood pressure is associated with trunk but not leg length (Regnault et al., 2014). Here, we found that the effects of height on disease risk due to leg or trunk length were similar. We found consistent effects of increased height across etiologically heterogeneous cancer subtypes, which implies that the mechanism could relate to the larger number of cells in taller individuals or a generalized growth phenotype. Notably there is minimal evidence of a correlation between the size of an organism and cancer risk (Peto’s paradox), suggesting that the number of cells hypothesis could influence cancer risk in humans but would not explain variation in cancer risk across different organisms (Caulin and Maley, 2011). Our Mendelian randomization estimates for the effects of height on a subset of cancers not strongly phenotypically associated with height (Green et al., 2011) were consistent with the combined cancer estimates, although we had limited power in this dataset because of the modest prevalence of the cancer subtypes.

The estimated effects of height on disease risk were relatively consistent between the Norwegian HUNT and UK Biobank studies. Contrastingly, the heterogeneity between UK Biobank and HUNT for analyses involving SBP and LDL-C suggests that some effects of height could be population specific. Alternatively, heterogeneity could relate to the variance in associations between adulthood height and early-life environmental confounders across countries (Perkins et al., 2016). Additional explanations could relate to the differences in biomarker measurement between studies (e.g., measuring LDL-C directly or using the Friedewald formula, differences in fasting level before samples were taken), selection bias (Munafò et al., 2016), or differences between the cohorts in terms of recruitment and participation. Further work is required to investigate if our findings generalize to non-European populations; biological mechanisms could be expected to be largely consistent across populations but context-specific (e.g., social) mechanisms could lead to geographic heterogeneity.

To conclude, using within-sibship Mendelian randomization, we showed that height has individual-level effects on risk of CHD and cancers as well as several biomarkers. Larger family datasets and additional analyses including two-step (Relton and Davey Smith, 2012) and multivariable Mendelian randomization (Burgess and Thompson, 2015) could be used to investigate the potential mediators of these relationships.

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 access@ukbiobank.ac.uk 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/ (copy archived at swh:1:rev:44d2435d841bc424b56eee2d8534d52dd4adf763).

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Author details

1. Laurence J Howe

   1. Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
   2. Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, United Kingdom
   3. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Software, Writing – original draft, Writing – review and editing

   For correspondence

   laurence.howe@bristol.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2819-9686

2. Ben Brumpton

   1. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
   2. HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
   3. Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

   Contribution

   Data curation, Funding acquisition, Supervision, Writing – review and editing

   Competing interests

   No competing interests declared

3. Humaira Rasheed

   1. Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
   2. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   Data curation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3331-5864

4. Bjørn Olav Åsvold

   1. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
   2. Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

   Contribution

   Data curation, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

5. George Davey Smith

   1. Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
   2. Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, United Kingdom

   Contribution

   Funding acquisition, Methodology, Supervision, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1407-8314

6. Neil M Davies

   1. Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
   2. Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, United Kingdom
   3. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   Funding acquisition, Investigation, Methodology, Supervision, Writing – review and editing

   For correspondence

   neil.davies@bristol.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2460-0508

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