Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits
Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits
Abstract 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. Motivated by previous epidemiological correlations observed between cardiometabolic traits and AD, 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. 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. Statistical colocalization with expression quantitative trait loci identified by the Genotype-Tissue Expression (GTEx) project identified additional candidate genes, 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. Overall, 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.
Tsao Philip S.、Ritchie Marylyn D.、Voight Benjamin F.、Jha Anupama、Damrauer Scott M.、Bone William P.、Klarin Derek、Chang Kyong-Mi、Assimes Themistocles L.、Siewert Katherine M.、the VA Million Veteran Project
VA Palo Alto Health Care System||Department of Medicine, Stanford University School of MedicineDepartment of Genetics, Perelman School of Medicine, University of Pennsylvania||Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania||Center for Precision Medicine, Perelman School of Medicine, University of PennsylvaniaCorporal Michael Crescenz VA Medical Center||Department of Genetics, Perelman School of Medicine, University of Pennsylvania||Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania||Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania||Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of PennsylvaniaDepartment of Computer and Information Science, School of Engineering and Applied Science, University of PennsylvaniaCorporal Michael Crescenz VA Medical Center||Department of Surgery, Perelman School of Medicine, University of PennsylvaniaGenomics and Computational Biology Graduate Group, Perelman School of Medicine, University of PennsylvaniaBoston VA Healthcare System||Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of MIT and HarvardCorporal Michael Crescenz VA Medical Center||Department of Surgery, Perelman School of Medicine, University of PennsylvaniaVA Palo Alto Health Care System||Department of Medicine, Stanford University School of MedicineGenomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Tsao Philip S.,Ritchie Marylyn D.,Voight Benjamin F.,Jha Anupama,Damrauer Scott M.,Bone William P.,Klarin Derek,Chang Kyong-Mi,Assimes Themistocles L.,Siewert Katherine M.,the VA Million Veteran Project.Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits[EB/OL].(2025-03-28)[2025-05-19].https://www.medrxiv.org/content/10.1101/2020.08.26.20179366.点此复制
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