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Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

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-ex...

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Main Authors: Küçükali, Fahri (Author) , Neumann, Alexander (Author) , Van Dongen, Jasper (Author) , De Pooter, Tim (Author) , Joris, Geert (Author) , De Rijk, Peter (Author) , Ohlei, Olena (Author) , Dobricic, Valerija (Author) , Bos, Isabelle (Author) , Vos, Stephanie J. B. (Author) , Engelborghs, Sebastiaan (Author) , De Roeck, Ellen (Author) , Vandenberghe, Rik (Author) , Gabel, Silvy (Author) , Meersmans, Karen (Author) , Tsolaki, Magda (Author) , Verhey, Frans (Author) , Martinez-Lage, Pablo (Author) , Tainta, Mikel (Author) , Frisoni, Giovanni (Author) , Blin, Oliver (Author) , Richardson, Jill C (Author) , Bordet, Régis (Author) , Alzheimer, 's Disease Neuroimaging Initiative (ADNI) (Author) , Scheltens, Philip (Author) , Popp, Julius (Author) , Peyratout, Gwendoline (Author) , Johannsen, Peter (Author) , Frölich, Lutz (Author) , Freund-Levi, Yvonne (Author) , Streffer, Johannes (Author) , Lovestone, Simon (Author) , Legido-Quigley, Cristina (Author) , Kate, Mara ten (Author) , Barkhof, Frederik (Author) , Zetterberg, Henrik (Author) , Bertram, Lars (Author) , Strazisar, Mojca (Author) , Visser, Pieter Jelle (Author) , Van Broeckhoven, Christine (Author) , Sleegers, Kristel (Author) , the, EMIF-AD Study Group (Author)
Format: Article (Journal)
Language:English
Published: June 2023
In: Alzheimer's and dementia
Year: 2023, Volume: 19, Issue: 6, Pages: 2317-2331
ISSN:1552-5279
DOI:10.1002/alz.12842
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/alz.12842
Verlag, kostenfrei, Volltext: http://alz.journals.onlinelibrary.wiley.com/doi/10.1002/alz.12842
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Author Notes:Fahri Küçükali, Alexander Neumann, Jasper Van Dongen, Tim De Pooter, Geert Joris, Peter De Rijk, Olena Ohlei, Valerija Dobricic, Isabelle Bos, Stephanie J. B. Vos, Sebastiaan Engelborghs, Ellen De Roeck, Rik Vandenberghe, Silvy Gabel, Karen Meersmans, Magda Tsolaki, Frans Verhey, Pablo Martinez-Lage, Mikel Tainta, Giovanni Frisoni, Oliver Blin, Jill C Richardson, Régis Bordet, 's Disease Neuroimaging Initiative (ADNI) Alzheimer, Philip Scheltens, Julius Popp, Gwendoline Peyratout, Peter Johannsen, Lutz Frölich, Yvonne Freund-Levi, Johannes Streffer, Simon Lovestone, Cristina Legido-Quigley, Mara ten Kate, Frederik Barkhof, Henrik Zetterberg, Lars Bertram, Mojca Strazisar, Pieter Jelle Visser, Christine Van Broeckhoven, Kristel Sleegers, the EMIF-AD Study Group
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Summary: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.
Item Description:Erstmals veröffentlicht: 04. Dezember 2022
Gesehen am 04.06.2024
Physical Description:Online Resource
ISSN:1552-5279
DOI:10.1002/alz.12842

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