eprintid: 10091061
rev_number: 30
eprint_status: archive
userid: 608
dir: disk0/10/09/10/61
datestamp: 2020-02-13 11:57:42
lastmod: 2021-10-05 00:47:46
status_changed: 2020-02-13 11:57:42
type: article
metadata_visibility: show
creators_name: Curtis, D
creators_name: Bakaya, K
creators_name: Sharma, L
creators_name: Bandyopadhyay, S
title: Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
divisions: D09
divisions: F99
keywords: C1R, LOAD, NDRG2, PIK3R1, PSEN1, TIAF1, tyrosine phosphatase
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
abstract: Previous studies have implicated common and rare genetic variants as risk factors for late‐onset Alzheimer's disease (LOAD). Here, weighted burden analysis was applied to over 10,000 exome‐sequenced subjects from the Alzheimer's Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7, and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R, and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Because PIK3R1 variants are expected to impair PI3K/Akt/GSK‐3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models, suggesting that this pathway is protective against Alzheimer's disease.
date: 2020-05
date_type: published
official_url: https://doi.org/10.1111/ahg.12375
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1749450
doi: 10.1111/ahg.12375
lyricists_name: Curtis, David
lyricists_id: DCURT26
actors_name: Austen, Jennifer
actors_id: JAUST66
actors_role: owner
full_text_status: public
publication: Annals of Human Genetics
volume: 84
number: 3
pagerange: 291-302
event_location: England
citation:        Curtis, D;    Bakaya, K;    Sharma, L;    Bandyopadhyay, S;      (2020)    Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways.                   Annals of Human Genetics , 84  (3)   pp. 291-302.    10.1111/ahg.12375 <https://doi.org/10.1111/ahg.12375>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10091061/1/Andres_SAPER%20theory%20and%20practise%20-%20Final%20Accepted%20Version.pdf