@article{82a6b87212d1487e90bf7d17c356641c,
title = "Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred",
abstract = "INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.",
keywords = "AAO, ACE, AOO, Alzheimer, CLU, E280A, HS3ST1, HSPG2, LRP1B, PSEN1, SIAH3, TSPAN10, TSPAN14, ZC3H13, age of onset, amyloid, clusterin, heparin sulfate, tetraspanin",
author = "Cochran, {Jesse Nicholas} and Juliana Acosta-Uribe and Esposito, {Bianca T.} and Lucia Madrigal and David Aguill{\'o}n and Giraldo, {Margarita M.} and Taylor, {Jared W.} and Joseph Bradley and Brian Fulton-Howard and Andrews, {Shea J.} and Natalia Acosta-Baena and Diana Alzate and Garcia, {Gloria P.} and Francisco Piedrahita and Lopez, {Hugo E.} and Anderson, {Ashlyn G.} and Ivan Rodriguez-Nunez and Kevin Roberts and I. Dominantly and Devin Absher and Myers, {Richard M.} and Beecham, {Gary W.} and Christiane Reitz and Rizzardi, {Lindsay F.} and Fernandez, {Maria Victoria} and Goate, {Alison M.} and Carlos Cruchaga and Renton, {Alan E.} and Francisco Lopera and Kosik, {Kenneth S.}",
note = "Funding Information: We thank the patients and their caregivers for their generous contributions to this study. We thank other members of the GNA for their contributions to the study of this cohort, which made this study possible. We thank Nithesh Perumal for assisting with pedigree reconstruction. Replication statistics were obtained from publicly available data for National Institute on Aging Genetics of Alzheimer's Disease (NIAGADS) project NG00075 and controlled access data from NIAGADS projects NG00048 and NG00058 and the Synapse AD Knowledge portal (Synapse ID: syn25871263). More extensive acknowledgement details for DIAN, IGAP, ADDS, and ADGC are provided in the supplemental acknowledgements. Grant and other financial support for this study overall and for particular investigators related to this study is detailed in the Funding section. J. Nicholas Cochran has consulted for Caraway Therapeutics. Richard M. Myers is a member of the board of directors for the Coalition for the Life Sciences and is a science advisor for Decheng Capital, Accuragen, iRepertoire, IMIDomics, Inc., iCubate, and Sentieon. Carlos Cruchaga has consulted for Circular Genomics and Alector, has received travel support from Somalogic, has a leadership or fiduciary role and holds stock or stock options in Vivid Genetics and Circular Genomics, and has received support not related to this study from GSK, Alector, Eisai, an anonymous foundation, Biogen, and Parabon. All other authors declared no relevant competing interests. Funding was provided by the HudsonAlpha Memory and Mobility Program, the Larry L. Hillblom Foundation, the Rainwater Foundation, National Institutes of Health Grant 4R00AG068271 (Cochran), National Institute on Aging, the Alzheimer's Association, and the Michael J. Fox Foundation (Cruchaga), 1R56AG062479‐01 and 5U54NS100717‐04 (Kosik), and the Sustainability Program of the University of Antioquia (Lopera). 18 16 17 Publisher Copyright: {\textcopyright} 2023 Alzheimer's Association.",
year = "2023",
doi = "10.1002/alz.13021",
language = "English",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "John Wiley & Sons Inc.",
}