eprintid: 10039768
rev_number: 33
eprint_status: archive
userid: 608
dir: disk0/10/03/97/68
datestamp: 2017-12-11 14:09:33
lastmod: 2021-09-23 22:36:17
status_changed: 2017-12-11 14:09:33
type: article
metadata_visibility: show
creators_name: Patel, T
creators_name: Brookes, KJ
creators_name: Turton, J
creators_name: Chaudhury, S
creators_name: Guetta-Baranes, T
creators_name: Guerreiro, R
creators_name: Bras, J
creators_name: Hernandez, D
creators_name: Singleton, A
creators_name: Francis, PT
creators_name: Hardy, J
creators_name: Morgan, K
title: Whole‐exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F86
keywords: Alzheimer's disease, Whole-exome sequencing, burden analysis, polygenic risk score
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
abstract: AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent GWAS have uncovered 20 new loci for AD risk, however these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single variant association and gene burden tests were performed for 76,640 non-singleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single variant association and burden analysis was also carried out on variants in known AD and other neurologic dementia genes. RESULTS: Tentative single variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P=3.4x10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P<0.05) but did not withstand correction for multiple testing. APOE (P=0.02) and CLU (P=0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3,268 variants, sex, age at death and APOE ε4 and ε2 status as predictors. This article is protected by copyright. All rights reserved.
date: 2018-08
date_type: published
official_url: https://doi.org/10.1111/nan.12452
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1513350
doi: 10.1111/nan.12452
lyricists_name: Hardy, John
lyricists_name: Louro Guerreiro, Rita
lyricists_name: Smalley, June
lyricists_name: Tomas Bras, Jose
lyricists_id: JHARD28
lyricists_id: RJLOU51
lyricists_id: JASMA87
lyricists_id: JMTOM86
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Neuropathology and Applied Neurobiology
volume: 44
number: 5
pagerange: 506-521
event_location: England
issn: 1365-2990
citation:        Patel, T;    Brookes, KJ;    Turton, J;    Chaudhury, S;    Guetta-Baranes, T;    Guerreiro, R;    Bras, J;                     ... Morgan, K; + view all <#>        Patel, T;  Brookes, KJ;  Turton, J;  Chaudhury, S;  Guetta-Baranes, T;  Guerreiro, R;  Bras, J;  Hernandez, D;  Singleton, A;  Francis, PT;  Hardy, J;  Morgan, K;   - view fewer <#>    (2018)    Whole‐exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.                   Neuropathology and Applied Neurobiology , 44  (5)   pp. 506-521.    10.1111/nan.12452 <https://doi.org/10.1111/nan.12452>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10039768/1/Patel_et_al-2017-Neuropathology_and_Applied_Neurobiology.pdf