Journal
ALZHEIMERS & DEMENTIA
Volume -, Issue -, Pages -Publisher
WILEY
DOI: 10.1002/alz.12842
Keywords
Alzheimer's disease; biomarkers; endophenotypes; rare coding variants; whole-exome sequencing
Categories
Funding
- EMIF
- 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 Union [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 Research Foundation [SNF 320030_141179]
- Synapsis Foundation - Alzheimer Research Switzerland [2017-PI01]
- University of Antwerp Research Fund
- Swedish Research Council [2018-02532]
- European Research Council [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
- Stiftelsen for Gamla Tjanarinnor
- Hjarnfonden, Sweden [FO2019-0228]
- 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)
- Petrus and Augusta Hedlunds Foundation
- Gun och Bertil Stohnes Foundation
- Loo and Hans Osterman Foundation
- Demensforbundet, Brain Foundation Hjarnfonden [FO2018-0315]
- Region Orebro lan
- Demensfonden, Stockholm and Nyckelfonden Region Orebro Lan
- ADNI - Alzheimer's DiseaseNeuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd
- Fujirebio
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Merck Co., Inc.
- Meso Scale Diagnostics
- NeuroRx Research
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Takeda Pharmaceutical Company
- Canadian Institutes of Health Research
- ADNI clinical sites in Canada
- Foundation for the National Institutes of Health
- Northern California Institute for Research and Education
- Laboratory for Neuro Imaging at the University of Southern California
- Alzheimer's DiseaseNeuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Cogstate
- Eisai Inc.
- EuroImmun
- F. Hoffmann-La Roche Ltd
- Genentech, Inc.
- GE Healthcare
- IXICO Ltd.
- Lumosity
- Lundbeck
- NeuroRx Research
- Neurotrack Technologies
- Pfizer Inc.Piramal Imaging
- Servier
- Transition Therapeutics
- DNI clinical sites in Canada
Ask authors/readers for more resources
In this study, the association between rare genetic variation and AD-related biomarker traits was investigated. Several novel gene-trait associations were identified, shedding light on the role of rare coding variation in the pathophysiological processes of AD.
IntroductionDespite 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. MethodsWe 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). ResultsMutation 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. DiscussionThe 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.
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