Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.

Autor: Bone WP; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Siewert KM; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Jha A; Department of Computer and Information Science, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, USA., Klarin D; Boston VA Healthcare System, Boston, MA, 02130, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Damrauer SM; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, PA, 19104, Philadelphia, USA.; Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, 19104, USA.; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Chang KM; Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, 19104, USA.; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Tsao PS; VA Palo Alto Health Care System, Palo Alto, CA, 94550, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA., Assimes TL; VA Palo Alto Health Care System, Palo Alto, CA, 94550, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA., Ritchie MD; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Center for Precision Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Voight BF; Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu.; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu.; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Alzheimer's research & therapy [Alzheimers Res Ther] 2021 Feb 04; Vol. 13 (1), pp. 34. Date of Electronic Publication: 2021 Feb 04.
DOI: 10.1186/s13195-021-00773-z
Abstrakt: 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.
Databáze: MEDLINE
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