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

Abstract

Taller people have lower risk of coronary heart disease but higher risk of many cancers. Mendelian randomization studies in unrelated individuals have suggested that these relationships are potentially causal. However, Mendelian randomization estimates from samples of unrelated individuals are sensitive to demography (population stratification, assortative mating) and familial (indirect genetic) effects. Height could influence disease risk via anatomic and physiological effects of height (e.g., number of cells or the bore of arteries) or previous results may have been confounded by early-life environmental factors (e.g., parental socioeconomic position and nutrition). In this study, we performed within-sibship Mendelian randomization analyses using 77,757 siblings, a design robust against demography and indirect genetic effects of parents. 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%). 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. 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.