A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program

• Type of Material: Article
• Authors: Sridharan Raghavan, Veterans Affairs Eastern Colorado Healthcare System; Jie Huang, Southern University of Science and Technology; Catherine Tcheandjieu, VA Palo Alto Health Care System; Jennifer E. Huffman, VA Medical Center; Elizabeth Litkowski, Veterans Affairs Eastern Colorado Healthcare System; Chang Liu, Atlanta VA Medical Center; Yuk-Lam A. Ho, VA Medical Center; Haley Hunter-Zinck, VA Medical Center; Hongyu Zhao, VA Connecticut Healthcare System; Eirini Marouli, Barts and The London School of Medicine and Dentistry; Kari E. North, University of North Carolina at Chapel Hill; Ethan Lange, University of Colorado Anschutz Medical Campus; Leslie A. Lange, University of Colorado Anschutz Medical Campus; Benjamin F. Voight, VA Medical Center; J. Michael Gaziano, VA Medical Center; Saiju Pyarajan, VA Medical Center; Elizabeth R. Hauser, VA Palo Alto Health Care System; Philip S. Tsao, Durham VA Health Care System; Peter Wilson, Emory University; Kyong-Mi Chang, VA Medical Center; Kelly Cho, VA Medical Center; Christopher J. ODonnell, VA Medical Center; Yan Sun, Emory University; Themistocles L. Assimes, VA Palo Alto Health Care System
• Language: English
• Date: 2022-06-02
• Publisher: PLoS
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pgen.1010193
• Title of Journal or Parent Work: PLoS Genetics
• Volume: 18
• Issue: 6
• Start Page: e1010193
• End Page: e1010193
• Grant/Funding Information: This work was supported by funding from the US Department of Veterans Affairs (https://www.research.va.gov/) MVP Program awards MVP001 I01-BX004821 (YH, KC, PWFW) and MVP003/028 I01-BX003362 (CT, PST, KMC, TLA); by the US Department of Veterans Affairs (https://www.research.va.gov/) award IK2-CX001907 (SR); by funds from the Boettcher Foundation’s Webb-Waring Biomedical Research Program (https://boettcherfoundation.org/webb-waring-biomedical-research/) (SR); by the US National Institutes of Health, National Institute for Diabetes, Digestive, and Kidney Diseases (https://www.niddk.nih.gov/research-funding) awards R01DK122503 (KEN), R01DK101855 (KEN), DK101478 (BFV), and DK126194 (BFV); by the US National Institutes of Health, National Human Genome Research Institute (https://www.genome.gov/research-funding) awards R01HG010297 (KEN) and R01HG009974 (KEN); by the US National Institutes of Health, National Heart, Lung, and Blood Institute (https://www.nhlbi.nih.gov/grants-and-training) awards R01HL142302 (KEN) and R01HL143885 (KEN); and by a Linda Pechenick Montague Investigator award (BFV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: Atrial Fibrillation; Adult; Hypertension; Veterans; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans
• Research Categories: Biology, Genetics

Abstract

Background Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. Methods and findings Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. Conclusions We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.