Journal article
Whole-genome sequencing reveals new Alzheimer's disease–associated rare variants in loci related to synaptic function and neuronal development
D Prokopenko, SL Morgan, K Mullin, O Hofmann, B Chapman, R Kirchner, S Amberkar, I Wohlers, C Lange, W Hide, L Bertram, RE Tanzi
Alzheimer S and Dementia | WILEY | Published : 2021
DOI: 10.1002/alz.12319
Abstract
Introduction: Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permits genome-wide analyses to identify rare variants contributing to AD risk. Methods: We performed single-variant and spatial clustering–based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family-based WGS-based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals. Results: We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implic..
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Awarded by National Institute of Mental Health
Funding Acknowledgements
The authors would like to thank the staff from the National Institute of Mental Health (NIMH) Divisions of Clinical and Treatment Research (DCTR) and Epidemiology and Services Research (DESR), including David Shore, MD, Mary Farmer, MD, MPH, Debra Wynne, MSW, Steven 0. Moldin, PhD, Darrell G. Kirch, MD (1989-1994), Nancy E. Maestri, PhD (1992-1994), William Huber (1989-1995), Pamela Wexler (1995-), and Darrel A. Regier, MD, MPH. They would also like to thank the study staff at all three sites and the data management staff at SRA Technologies, Inc., particularly Cheryl McDonnell, PhD, for the care and attention that they paid to all aspects of the study. The authors are also extremely grateful to the families whose participation made this work possible. We would like to thank Dr. Ioannis Vlachos and Leinal Sejour, Beth Israel Hospital Non-coding RNA precision diagnostics and therapeutics core of the Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, for their help in interpretation of non-coding genome and ncRNA genes. This study was supported by the Cure Alzheimer's Fund, and the following federal grants: U24AG026395 (NIA-LOAD Family Study); U24AG021886 (National Cell Repository for Alzheimer's Disease); P50AG08702 (Boston University and Columbia University); P30AG028377 (Duke University); P30AG010133 (Indiana University); PO1 AG05138 (Massachusetts General Hospital; Mayo Clinic, Rochester; Mayo Clinic, Jacksonville; and Mount Sinai School of Medicine); and P30AG010124 (Northwestern University Medical School; Oregon Health and Science University; Rush University Medical Center; University of Alabama at Birmingham; David Geffen School of Medicine, University of California, Los Angeles; University of Kentucky, Lexington; University of Pennsylvania; University of Pittsburgh; University of Southern California; The University of Texas Southwestern Medical Center; University of Washington; and Washington University School of Medicine). This work was also supported in part by the National Institute for Health Research (NIHR) Sheffield Biomedical Research Centre (Translational Neuroscience)/NIHR Sheffield Clinical Research Facility and the Cure Alzheimer's Fund (Alzheimer's Disease Research Foundation) (W.A.H.). Please refer to the Supplementary Note for additional acknowledgements.