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

Abstract

Background: 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. Methods: We sought to address this by harnessing human genetic data to separate the independent effects of childhood and adulthood height using an approach known as lifecourse Mendelian randomization (MR). We analysed 5 cardiovascular disease endpoints (coronary artery disease (CAD), stroke, peripheral arterial disease (PAD), atrial fibrillation (AF) and thoracic aortic aneurysm (TAA)) using findings from large-scale genome-wide consortia (n=184,305 to 1,030,836). Results: Protective effects of taller childhood height on risk of later life CAD (OR=0.78 per change in height category, 95% CI=0.70 to 0.86, P=4x10-10) and stroke (OR=0.93, 95% CI=0.86 to 1.00, P=0.03) 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 AF (OR=1.61, 95% CI=1.42 to 1.79, P=5x10-7) and TAA (OR=1.55, 95% CI=1.16 to 1.95, P=0.03) were found even after accounting for adulthood height in the multivariable model. Conclusions: The protective effect of childhood height on risk of CAD and stroke is largely attributed to the causal pathway involving adulthood height, which may therefore be explained by taller children typically becoming taller individuals in later life. Conversely, the independent effect of childhood height on increased risk of AF and TAA may point towards developmental mechanisms in early life which confer a lifelong risk on these disease outcomes.