학술논문
Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits
Document Type
Report
Author
Bone, William P.; Siewert, Katherine M.; Jha, Anupama; Klarin, Derek; Damrauer, Scott M.; Ballas, Zuhair K.; Bhushan, Sujata; Boyko, Edward J.; Cohen, David M.; Concato, John; Constans, Joseph I.; Dellitalia, Louis J.; Fayad, Joseph M.; Fernando, Ronald S.; Florez, Hermes J.; Gaddy, Melinda A.; Gappy, Saib S.; Gibson, Gretchen; Godschalk, Michael; Greco, Jennifer A.; Gupta, Samir; Gutierrez, Salvador; Hammer, Kimberly D.; Hamner, Mark B.; Harley, John B.; Hung, Adriana M.; Huq, Mostaqul; Hurley, Robin A.; Iruvanti, Pran R.; Ivins, Douglas J.; Jacono, Frank J.; Jhala, Darshana N.; Kaminsky, Laurence S.; Kinlay, Scott; Klein, Jon B.; Liangpunsakul, Suthat; Lichy, Jack H.; Mastorides, Stephen M.; Mathew, Roy O.; Mattocks, Kristin M.; McArdle, Rachel; Meyer, Paul N.; Meyer, Laurence J.; Moorman, Jonathan P.; Morgan, Timothy R.; Murdoch, Maureen; Nguyen, Xuan-Mai T.; Okusaga, Olaoluwa O.; Oursler, Kris-Ann K.; Ratcliffe, Nora R.; Rauchman, Michael I.; Robey, R. Brooks; Ross, George W.; Servatius, Richard J.; Sharma, Satish C.; Sherman, Scott E.; Sonel, Elif; Sriram, Peruvemba; Stapley, Todd; Striker, Robert T.; Tandon, Neeraj; Villareal, Gerardo; Wallbom, Agnes S.; Wells, John M.; Whittle, Jeffrey C.; Whooley, Mary A.; Xu, Junzhe; Yeh, Shing-Shing; Aslan, Michaela; Brewer, Jessica V.; Brophy, Mary T.; Connor, Todd; Argyres, Dean P.; Do, Nhan V.; Hauser, Elizabeth R.; Humphries, Donald E.; Selva, Luis E.; Shayan, Shahpoor; Stephens, Brady; Whitbourne, Stacey B.; Zhao, Hongyu; Moser, Jennifer; Beckham, Jean C.; Breeling, Jim L.; Romero, J. P. Casas; Huang, Grant D.; Ramoni, Rachel B.; Muralidhar, Sumitra; Aguayo, Samuel M.; Ahuja, Sunil K.; Pyarajan, Saiju; Sun, Yan V.; Cho, Kelly; Gaziano, J. Michael; Wilson, Peter W.; O'Donnell, Christopher J.
Source
Alzheimer's Research & Therapy. February 4, 2021, Vol. 13 Issue 1
Subject
Language
English
ISSN
1758-9193
Abstract
Background Identification of genetic risk factors that are shared between Alzheimer'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: Pleiotropy, Cardiometabolic traits, Multi-trait GWAS, Colocalization
Author(s): William P. Bone[sup.1] , Katherine M. Siewert[sup.1] , Anupama Jha[sup.2] , Derek Klarin[sup.3,4,5] , Scott M. Damrauer[sup.6,7,8] , Zuhair K. Ballas[sup.] , Sujata Bhushan[sup.] , Edward J. Boyko[sup.] , [...]
Author(s): William P. Bone[sup.1] , Katherine M. Siewert[sup.1] , Anupama Jha[sup.2] , Derek Klarin[sup.3,4,5] , Scott M. Damrauer[sup.6,7,8] , Zuhair K. Ballas[sup.] , Sujata Bhushan[sup.] , Edward J. Boyko[sup.] , [...]