Michael G. Levin, Renae Judy, Dipender Gill, Marijana Vujkovic, Shefali S. Verma, Yuki Bradford, Regeneron Genetics Center , Marylyn D. Ritchie, Matthew C. Hyman, Saman Nazarian, Daniel J. Rader, Benjamin F. Voight, Scott M. Damrauer
Abstract
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.
Introduction
Atrial fibrillation is a common cardiac arrhythmia, with a population prevalence of 0.5%, affecting more than 33 million individuals worldwide [1]. A number of risk factors are associated with atrial fibrillation, including chronic diseases like chronic kidney disease, heart failure, thyroid disease, obesity, obstructive sleep apnea, sleep apnea, and valvular heart disease, as well as cardiac surgery, smoking, and anthropometric factors [2–5]. Recent studies have identified both common and rare genetic variants at more than 100 independent loci contributing to the incidence of atrial fibrillation, and heritability is estimated at 20% [6–8]. Even with treatment, affected individuals are at risk of cardioembolic stroke, heart failure, and death [2].
Discussion
In this study we used both population- and individual-level genetic information to test the association between height and atrial fibrillation. At the population level, there was a strong causal association between genetic determinants of height and risk of atrial fibrillation. This finding was robust to multiple sensitivity analyses of the MR methods and the genetic instrument for height. Observational analysis at the individual level identified a strong association between height and increased risk of atrial fibrillation, and decreased risk of coronary artery disease. MR analysis at both the population and individual levels suggested that height remains a causal risk factor for atrial fibrillation even after adjustment for other traditional risk factors.
Citation: Levin MG, Judy R, Gill D, Vujkovic M, Verma SS, Bradford Y, et al. (2020) Genetics of height and risk of atrial fibrillation: A Mendelian randomization study. PLoS Med 17(10): e1003288. https://doi.org/10.1371/journal.pmed.1003288
Academic Editor: Michiel Rienstra, University of Groningen, University Medical Center Groningen, NETHERLANDS
Received:January 5, 2020; Accepted: September 3, 2020; Published: October 8, 2020.
Copyright:© 2020 Levin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: GWAS summary statistics for height are publicly available, and can be downloaded from the GIANT consortium website (https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files). Summary statistics for atrial fibrillation were contributed by the AFGen consortium (http://afgen.org), are publicly available, and may be downloaded from the Variant to Function Knowledge Portal (http://www.kp4cd.org/datasets/v2f). Individual-level data from the Penn Medicine BioBank are not publicly available due to their sensitive nature, however the data may be made available with the appropriate ethical approval and data sharing agreements (biobank@upenn.edu).
Funding: BFV was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK101478; https://www.niddk.nih.gov/) and a Linda Pechenik Montague Investigator Award (upenn.edu). SMD was supported by the US Department of Veterans Affairs (IK2-CX001780; VA.gov). This publication does not represent the views of the Department of Veterans Affairs or the United States government. DG was supported by funding from the Wellcome Trust (https://wellcome.ac.uk/). Genetic sequencing of Penn Medicine Biobank participants was performed in collaboration with Regeneron Genetics Center (https://www.regeneron.com/genetics-center), who also reviewed the manuscript but had no role in study design, data analysis, or decision to publish. The other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests:The authors have declared that no competing interests exist.
Abbreviations: GRS, genetic risk score; GWAS, genome-wide association study; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MR, Mendelian randomization; OR, odds ratio; PheWAS, phenome-wide association study.
