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Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer’s disease

Patel, Tulsi; Brookes, Keeley J.; Turton, James; Chaudhury, Sultan; Guetta-Baranes, Tamar; Guerreiro, Rita; Bras, Jose; Hernandez, Dena; Singleton, Andrew; Francis, Paul T.; Hardy, John; Morgan, Kevin

Authors

Tulsi Patel Tulsi.Patel@nottingham.ac.uk

Keeley J. Brookes

James Turton

Sultan Chaudhury Sultan.Chaudhury@nottingham.ac.uk

Tamar Guetta-Baranes

Rita Guerreiro

Jose Bras

Dena Hernandez

Andrew Singleton

Paul T. Francis

John Hardy

KEVIN MORGAN kevin.morgan@nottingham.ac.uk
Professor of Human Genomics and Molecular Genetics



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

Citation

Patel, T., Brookes, K. J., Turton, J., Chaudhury, S., Guetta-Baranes, T., Guerreiro, R., …Morgan, K. (2019). 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), 506-521. doi:10.1111/nan.12452

Journal Article Type Article
Acceptance Date Nov 22, 2017
Online Publication Date Nov 27, 2017
Publication Date 2019-08
Deposit Date Nov 23, 2017
Publicly Available Date Nov 28, 2018
Journal Neuropathology and Applied Neurobiology
Print ISSN 0305-1846
Electronic ISSN 0305-1846
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 44
Issue 5
Pages 506-521
DOI https://doi.org/10.1111/nan.12452
Keywords Whole-exome sequencing, Alzheimer's disease, burden analysis, polygenic risk score
Public URL http://eprints.nottingham.ac.uk/id/eprint/48334
Publisher URL http://onlinelibrary.wiley.com/doi/10.1111/nan.12452/abstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This is the peer reviewed version of the following article:Patel, T., Brookes, K. J., Turton, J., Chaudhury, S., Guetta-Baranes, T., Guerreiro, R., Bras, J., Hernandez, D., Singleton, A., Francis, P. T., Hardy, J. and Morgan, K. (), Whole-exome sequencing of the BDR cohort: Evidence to support the role of the PILRA gene in Alzheimer's disease. Neuropathol Appl Neurobiol. Accepted Author Manuscript. doi:10.1111/nan.12452, which has been published in final form at http://onlinelibrary.wi...111/nan.12452/abstract. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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