Mendelian randomization analyses reveal mediating factors of the causal effect of height on coronary artery disease

Abstract

AbstractAn inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested evidence that this association may be causal. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized the largest set of genetic instruments for human stature to date, comprising >2,000 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (∼6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 2.1x10-2). We observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest that height does not add meaningful clinical impact on CAD risk prediction beyond established risk factors.