Genetics of height and risk of atrial fibrillation: A Mendelian randomization study

Background Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation. Methods and findings In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10−42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55–72; 38% female; recruitment 2008–2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations. Conclusions In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.
Scott Damrauer and colleagues investigate genetic evidence for a potential causal relationship between height and risk of atrial fibrillation.
Author summary Why was this study done? Studies have identified height as a risk factor for atrial fibrillation, a common abnormal heart rhythm. Whether being taller actually elevates risk of atrial fibrillation, or if this association is an artifact of prior study designs, remains unclear. What did the researchers do and find? We examined randomly allocated genetic variants associated with height within the Mendelian randomization framework to study the effects of height on risk of atrial fibrillation. Genetic variants associated with taller stature were also associated with increased risk of atrial fibrillation. This finding was consistent across multiple analysis methods, including when accounting for other known atrial fibrillation risk factors. What do these findings mean? Taller individuals are likely to be at increased risk of atrial fibrillation. Future research is needed to better define the pathways connecting height to atrial fibrillation.