@article{bccc41feed7f46788dd87f519da1b289,
title = "Multi-trait association studies discover pleiotropic loci between Alzheimer{\textquoteright}s disease and cardiometabolic traits",
abstract = "Background: Identification of genetic risk factors that are shared between Alzheimer{\textquoteright}s disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. Methods: We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. Results: We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Conclusion: Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.",
keywords = "Cardiometabolic traits, Colocalization, Multi-trait GWAS, Pleiotropy",
author = "{the VA Million Veteran Program} and Bone, {William P.} and Siewert, {Katherine M.} and Anupama Jha and Derek Klarin and Damrauer, {Scott M.} and Ballas, {Zuhair K.} and Sujata Bhushan and Boyko, {Edward J.} and Cohen, {David M.} and John Concato and Constans, {Joseph I.} and Dellitalia, {Louis J.} and Fayad, {Joseph M.} and Fernando, {Ronald S.} and Florez, {Hermes J.} and Gaddy, {Melinda A.} and Gappy, {Saib S.} and Gretchen Gibson and Michael Godschalk and Greco, {Jennifer A.} and Samir Gupta and Salvador Gutierrez and Hammer, {Kimberly D.} and Hamner, {Mark B.} and Harley, {John B.} and Hung, {Adriana M.} and Mostaqul Huq and Hurley, {Robin A.} and Iruvanti, {Pran R.} and Ivins, {Douglas J.} and Jacono, {Frank J.} and Jhala, {Darshana N.} and Kaminsky, {Laurence S.} and Scott Kinlay and Klein, {Jon B.} and Suthat Liangpunsakul and Lichy, {Jack H.} and Mastorides, {Stephen M.} and Mathew, {Roy O.} and Mattocks, {Kristin M.} and Rachel McArdle and Meyer, {Paul N.} and Meyer, {Laurence J.} and Moorman, {Jonathan P.} and Morgan, {Timothy R.} and Maureen Murdoch and Nguyen, {Xuan Mai T.} and Okusaga, {Olaoluwa O.} and Oursler, {Kris Ann K.} and Sherman, {Scott E.}",
note = "Funding Information: This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by the Department of Veterans Affairs Office of R&D award I01-BX003362 (to P.S.T. and K.M.C) and IK2-CX001780 (to S.M.D). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. This work was supported by the American Heart Association (20PRE35120109 to W.P.B.), the National Institutes of Health (DK101478 to B.F.V. and P50GM115318-01 to M.D.R.), and a Linda Pechenik Montague Investigator Award (to B.F.V.). Funding Information: We want to thank Tiffany R. Bellomo and Jason E. Miller for sharing their medical and phenotypic knowledge. The VA Million Veteran Program: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 16Iowa City VA Health Care System, Iowa City, IA, USA, 17VA North Texas Health Care System, Dallas, TX, USA, 18VA Puget Sound Health Care System, Seattle, WA, USA, 19Portland VA Medical Center, Portland, OR, USA, 20VA Connecticut Healthcare System, West Haven, CT, USA, 21Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA, 22Birmingham VA Medical Center, Birmingham, AL, USA, 23VA Southern Nevada Healthcare System, North Las Vegas, NV, USA, 24VA Loma Linda Healthcare System, Loma Linda, CA, USA, 25Miami VA Health Care System, Miami, FL, USA, 26VA Eastern Kansas Health Care System, Leavenworth, KS, USA, 27John D. Dingell VA Medical Center, Detroit, MI, USA, 28Fayetteville VA Medical Center, Fayetteville, AR, USA, 29Richmond VA Medical Center, Richmond, VA, USA, 30Sioux Falls VA Health Care System, Sioux Falls, SD, USA, 31VA San Diego Healthcare System, San Diego, CA, USA, 32Edward Hines Jr. VA Medical Center, Hines, IL, USA, 33Fargo VA Health Care System, Fargo, ND, USA, 34Ralph H. Johnson VA Medical Center, Charleston, SC, USA, 35Cincinnati VA Medical Center, Cincinnati, OH, USA, 36VA Tennessee Valley Healthcare System, Nashville, TN, USA, 37VA Sierra Nevada Health Care System, Reno, NV, USA, 38W.G. (Bill) Hefner VA Medical Center, Salisbury, NC, USA, 39Hampton VA Medical Center, Hampton, VA, USA, 40Eastern Oklahoma VA Health Care System, Muskogee, OK, USA, 41VA Northeast Ohio Healthcare System, Cleveland, OH, USA, 42Philadelphia VA Medical Center, Philadelphia, PA, USA, 43VA Health Care Upstate New York, Albany, NY, USA, 44VA Boston Healthcare System, Boston, MA, USA, 45Louisville VA Medical Center, Louisville, KY, USA, 46Richard Roudebush VA Medical Center, Indianapolis, IN, USA, 47Washington DC VA Medical Center, Washington, D.C., USA, 48James A. Haley Veterans Hospital, Tampa, FL, USA, 49Columbia VA Health Care System, Columbia, SC, USA, 50Central Western Massachusetts Healthcare System, Leeds, MA, USA, 51Bay Pines VA Healthcare System, Bay Pines, FL, USA, 52Southern Arizona VA Health Care System, Tucson, AZ, USA, 53VA Salt Lake City Health Care System, Salt Lake City, UT, USA, 54James H. Quillen VA Medical Center, Johnson City, TN, USA, 55VA Long Beach Healthcare System, Long Beach, CA, USA. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1186/s13195-021-00773-z",
language = "English (US)",
volume = "13",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
publisher = "BioMed Central",
number = "1",
}