Abstract
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.
Original language | English |
---|---|
Journal | Alzheimer's and Dementia |
Volume | 19 |
Issue number | 6 |
Pages (from-to) | 2317-2331 |
Number of pages | 15 |
ISSN | 1552-5260 |
DOIs | |
Publication status | Published - 06.2023 |
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Alzheimer's and Dementia, Vol. 19, No. 6, 06.2023, p. 2317-2331.
Research output: Journal Articles › Journal articles › Research › peer-review
TY - JOUR
T1 - Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits
AU - Alzheimer's Disease Neuroimaging Initiative (ADNI)
AU - the EMIF-AD Study Group
AU - Küçükali, Fahri
AU - Neumann, Alexander
AU - Van Dongen, Jasper
AU - De Pooter, Tim
AU - Joris, Geert
AU - De Rijk, Peter
AU - Ohlei, Olena
AU - Dobricic, Valerija
AU - Bos, Isabelle
AU - Vos, Stephanie J.B.
AU - Engelborghs, Sebastiaan
AU - De Roeck, Ellen
AU - Vandenberghe, Rik
AU - Gabel, Silvy
AU - Meersmans, Karen
AU - Tsolaki, Magda
AU - Verhey, Frans
AU - Martinez-Lage, Pablo
AU - Tainta, Mikel
AU - Frisoni, Giovanni
AU - Blin, Oliver
AU - Richardson, Jill C.
AU - Bordet, Régis
AU - Scheltens, Philip
AU - Popp, Julius
AU - Peyratout, Gwendoline
AU - Johannsen, Peter
AU - Frölich, Lutz
AU - Freund-Levi, Yvonne
AU - Streffer, Johannes
AU - Lovestone, Simon
AU - Legido-Quigley, Cristina
AU - Kate, Mara ten
AU - Barkhof, Frederik
AU - Zetterberg, Henrik
AU - Bertram, Lars
AU - Strazisar, Mojca
AU - Visser, Pieter Jelle
AU - Van Broeckhoven, Christine
AU - Sleegers, Kristel
N1 - Funding Information: The authors thank the participants and families who took part in this research. The authors would also like to thank all people involved in data and sample collection and/or logistics across the different centers. EMIF: The present study was conducted as part of the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) project, which has received support from the Innovative Medicines Initiative Joint Undertaking under the European Medical Information Framework (EMIF) grant agreement no. 115372, the European Prevention of Alzheimer's Dementia (EPAD) grant no. 115736, and from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 666992, resources of which are composed of financial contributions from the European Union's Seventh Framework Program (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Association (EFPIA) companies' in-kind contribution. The Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study was funded by the European Commission within the fifth framework program (QLRT-2001-2455). The Beta Amyloid Oligomers in Early Diagnosis of AD and as Marker for Treatment Response (EDAR) study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian Gipuzkoa Alzheimer Project (GAP) study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant nos. 11020, 13007, and 15005). The Lausanne cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_141179), Synapsis Foundation - Alzheimer Research Switzerland (grant no. 2017-PI01). F.K. is recipient of a PhD fellowship of the University of Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (no. 2018-02532), the European Research Council (no. 681712), Swedish State Support for Clinical Research (no. ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (no. 201809-2016862), the AD Strategic Fund and the Alzheimer's Association (nos. ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. F.B. is supported by the National Institute for Health and Care Research (NIHR) biomedical research centre at University College London Hospitals (UCLH). This work was supported for Y.F-L. by grants from the Petrus and Augusta Hedlunds Foundation, the Gun och Bertil Stohnes Foundation, the Loo and Hans Osterman Foundation, the Demensförbundet, Brain Foundation “Hjärnfonden” (grant FO2018-0315), “Särfond 31 Forskning Senil demens,” Region Örebro län, “Stiftelsen for Gamla Tjänarinnor,” and Demensfonden, Stockholm and Nyckelfonden Region Örebro Län. ADNI: Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award no. W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: EMIF: The present study was conducted as part of the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) project, which has received support from the Innovative Medicines Initiative Joint Undertaking under the European Medical Information Framework (EMIF) grant agreement no. 115372, the European Prevention of Alzheimer's Dementia (EPAD) grant no. 115736, and from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 666992, resources of which are composed of financial contributions from the European Union's Seventh Framework Program (FP7/2007‐2013) and the European Federation of Pharmaceutical Industries and Association (EFPIA) companies' in‐kind contribution. The Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study was funded by the European Commission within the fifth framework program (QLRT‐2001‐2455). The Beta Amyloid Oligomers in Early Diagnosis of AD and as Marker for Treatment Response (EDAR) study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian Gipuzkoa Alzheimer Project (GAP) study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant nos. 11020, 13007, and 15005). The Lausanne cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_141179), Synapsis Foundation ‐ Alzheimer Research Switzerland (grant no. 2017‐PI01). F.K. is recipient of a PhD fellowship of the University of Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (no. 2018‐02532), the European Research Council (no. 681712), Swedish State Support for Clinical Research (no. ALFGBG‐720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (no. 201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (nos. ADSF‐21‐831376‐C, ADSF‐21‐831381‐C, and ADSF‐21‐831377‐C), the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019‐0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. F.B. is supported by the National Institute for Health and Care Research (NIHR) biomedical research centre at University College London Hospitals (UCLH). This work was supported for Y.F‐L. by grants from the Petrus and Augusta Hedlunds Foundation, the Gun och Bertil Stohnes Foundation, the Loo and Hans Osterman Foundation, the Demensförbundet, Brain Foundation “Hjärnfonden” (grant FO2018‐0315), “Särfond 31 Forskning Senil demens,” Region Örebro län, “Stiftelsen for Gamla Tjänarinnor,” and Demensfonden, Stockholm and Nyckelfonden Region Örebro Län. Funding Information: ADNI: Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database ( adni.loni.usc.edu ). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp‐content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf . Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award no. W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85144049519&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/91af5a36-9454-3a97-ad4e-f6fbe760ed9f/
U2 - 10.1002/alz.12842
DO - 10.1002/alz.12842
M3 - Journal articles
C2 - 36464806
AN - SCOPUS:85144049519
SN - 1552-5260
VL - 19
SP - 2317
EP - 2331
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 6
ER -