Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traitsDepartment of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
Netherlands Institute for Health Services Research, Utrecht, Netherlands.
Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neurology and Brussels Integrated Center for Brain and Memory (Bru-BRAIN), Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
University Hospital Leuven, Leuven, Belgium; Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
University Hospital Leuven, Leuven, Belgium; Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
University Hospital Leuven, Leuven, Belgium; Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Thessaloniki, Greece.
Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands; Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.
Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
Department of Psychiatry, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland; RCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital, Marseille, France.
Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevanage, United Kingdom.
Neuroscience & Cognition, CHU de Lille, University of Lille, Inserm, France.
Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands; Alzheimer's Disease Neuroimaging Initiative (ADNI).
Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, Zürich, Switzerland; Department of Psychiatry, Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
Clinical Drug Development, Novo Nordisk, Copenhagen, Denmark.
Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Department of Psychiatry, University of Oxford, Oxford, United Kingdom; Janssen Medical Ltd, High Wycombe, United Kingdom.
Steno Diabetes Center, Copenhagen, Denmark; Institute of Pharmaceutical Sciences, King's College London, London, United Kingdom.
Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands; Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands; Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, United Kingdom.
Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute, University College London, London, United Kingdom; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany; Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands; Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
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2023 (English)In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 19, no 6, p. 2317-2331Article in journal (Refereed) Published
Abstract [en]
INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.
METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).
RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.
DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.
Place, publisher, year, edition, pages
John Wiley & Sons, 2023. Vol. 19, no 6, p. 2317-2331
Keywords [en]
Alzheimer's disease, biomarkers, endophenotypes, rare coding variants, whole-exome sequencing
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:oru:diva-102658DOI: 10.1002/alz.12842ISI: 000899903900001PubMedID: 36464806Scopus ID: 2-s2.0-85144049519OAI: oai:DiVA.org:oru-102658DiVA, id: diva2:1718621
Funder
Swedish Research Council, 2018-02532Stiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, FO2019-0228 FO2018-0315Hedlund foundationGun och Bertil Stohnes StiftelseRegion Örebro CountyPfizer AB
Note
Funding agencies:
European Medical Information Framework for Alzheimer's Disease (EMIF-AD)
Innovative Medicines Initiative Joint Undertaking under the European Medical Information Framework (EMIF) 115372
European Prevention of Alzheimer's Dementia (EPAD) 115736
European Commission 860197
European Federation of Pharmaceutical Industries and Association (EFPIA) - European Commission within the fifth framework program QLRT-2001-2455
European Commission within the fifth framework program 37670
Department of Health of the Basque Government (allocation) 17.0.1.08.12.0000.2.454.01.41142.001
Stichting voor Alzheimer Onderzoek 11020 13007 15005
Swiss National Science Foundation (SNSF) SNF 320030_141179
Synapsis Foundation - Alzheimer Research Switzerland 2017-PI01
University of Antwerp Research Fund
European Commission European Research Council (ERC) 681712
Swedish State Support for Clinical Research ALFGBG-720931
Alzheimer Drug Discovery Foundation (ADDF), USA 201809-2016862
AD Strategic Fund
Alzheimer's Association
Olav Thon Foundation
Erling-Persson Family Foundation
UK Dementia Research Institute at University College London
National Institute for Health and Care Research (NIHR) biomedical research centre at University College London Hospitals (UCLH)
Instituto de Salud Carlos III
Demensfonden, Stockholm
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA U01 AG024904
DOD ADNI (Department of Defense) W81XWH-12-2-0012 United States Department of Health & Human Services
NIH National Institute on Aging (NIA) United States Department of Health & Human Services
NIH National Institute of Biomedical Imaging & Bioengineering (NIBIB)
Alzheimer's Drug Discovery Foundation
Araclon Biotech
Biogen
Bristol-Myers Squibb
CereSpir, Inc.
CogState Limited
Elan Pharmaceuticals, Inc.
Eli Lilly
EuroImmun
Hoffmann-La Roche
Fujirebio
Johnson & Johnson USA
Merck & Company
Meso Scale Diagnostics
NeuroRx Research
Novartis
Piramal Imaging
Takeda Pharmaceutical Company Ltd
Canadian Institutes of Health Research (CIHR)
ADNI clinical sites in Canada
United States Department of Health & Human Services National Institutes of Health (NIH) - USA Northern California Institute for Research and Education
Laboratory for Neuro Imaging at the University of Southern California
NIH National Institute of Neurological Disorders & Stroke (NINDS) U01 AG024904
NIH National Institute on Aging (NIA)
NIH National Institute of Biomedical Imaging & Bioengineering (NIBIB)
AbbVie
CogState Limited
Hoffmann-La Roche
Roche Holding
Genentech
General Electric
GE Healthcare
IXICO Ltd.
Lumosity
Lundbeck Corporation
NeuroRx Research; Neurotrack Technologies
Pfizer Inc.Piramal Imaging
Servier
Transition Therapeutics
DNI clinical sites in Canada
2022-12-132022-12-132023-12-08Bibliographically approved