@article{218ae4e0765440a6a2c6c89afb804f1a,
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 Ratcliffe, {Nora R.} and Rauchman, {Michael I.} and Robey, {R. Brooks} and Ross, {George W.} and Servatius, {Richard J.} and Sharma, {Satish C.} and Sherman, {Scott E.} and Elif Sonel and Peruvemba Sriram and Todd Stapley and Striker, {Robert T.} and Neeraj Tandon and Gerardo Villareal and Wallbom, {Agnes S.} and Wells, {John M.} and Whittle, {Jeffrey C.} and Whooley, {Mary A.} and Junzhe Xu and Yeh, {Shing Shing} and Michaela Aslan and Brewer, {Jessica V.} and Brophy, {Mary T.} and Todd Connor and Argyres, {Dean P.} and Do, {Nhan V.} and Hauser, {Elizabeth R.} and Humphries, {Donald E.} and Selva, {Luis E.} and Shahpoor Shayan and Brady Stephens and Whitbourne, {Stacey B.} and Hongyu Zhao and Jennifer Moser and Beckham, {Jean C.} and Breeling, {Jim L.} and Romero, {J. P.Casas} and Huang, {Grant D.} and Ramoni, {Rachel B.} and Sumitra Muralidhar and Aguayo, {Samuel M.} and Ahuja, {Sunil K.} and Saiju Pyarajan and Sun, {Yan V.} and Kelly Cho and Gaziano, {J. Michael} and Wilson, {Peter W.} and O{\textquoteright}Donnell, {Christopher J.} and Chang, {Kyong Mi} and Tsao, {Philip S.} and Assimes, {Themistocles L.} and Ritchie, {Marylyn D.} and Voight, {Benjamin F.}",
note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1186/s13195-021-00773-z",
language = "English",
volume = "13",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
number = "1",
}