Effects of childhood and adult height on later life cardiovascular disease risk estimated through Mendelian randomization

Taller individuals are at elevated and protected risk of various cardiovascular disease endpoints. Whether this is due to a direct consequence of their height during childhood, a long-term effect of remaining tall throughout the lifecourse, or confounding by other factors, is unknown. We sought to address this by harnessing human genetic data from the UK Biobank to separate the independent effects of childhood and adulthood height using an approach known as lifecourse Mendelian randomization (MR). Protective effects of taller childhood height on risk of later life coronary artery disease (OR = 0.78 per change in height category, 95% CI = 0.70 to 0.86, P = 4 × 10 - 10) and stroke (OR = 0.93, 95% CI = 0.86 to 1.00, P = 0.03) using data from large-scale consortia were found using a univariable model, although evidence of these effects attenuated in a multivariable setting upon accounting for adulthood height. In contrast, direct effects of taller childhood height on increased risk of later life atrial fibrillation (OR = 1.61, 95% CI = 1.42 to 1.79, P = 5 × 10 - 7) and thoracic aortic aneurysm (OR = 1.55, 95% CI = 1.16 to 1.95, P = 0.03) were found even after accounting for adulthood height. Evidence for both of these direct effects was replicated in the Million Veterans Program. The protective effect of childhood height on risk of coronary artery disease and stroke can be largely explained by taller children typically becoming taller individuals in later life. Conversely, the independent effect of childhood height on increased risk of atrial fibrillation and thoracic aortic aneurysm may point towards developmental mechanisms in early life which confer a lifelong risk on these disease outcomes.