Küçükali, Fahri;
Neumann, Alexander;
Van Dongen, Jasper;
De Pooter, Tim;
Joris, Geert;
De Rijk, Peter;
Ohlei, Olena;
... EMIF-AD, Study Group; + view all
(2022)
Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.
Alzheimer's & Dementia
10.1002/alz.12842.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/alz.12842 |
| Publisher version: | https://doi.org/10.1002/alz.12842 |
| Language: | English |
| Additional information: | © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Alzheimer's disease, biomarkers, endophenotypes, rare coding variants, whole-exome sequencing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Brain Repair and Rehabilitation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10161603 |
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