dc.contributor.author | Sassi, C | |
dc.contributor.author | Ridge, PG | |
dc.contributor.author | Nalls, MA | |
dc.contributor.author | Gibbs, R | |
dc.contributor.author | Ding, J | |
dc.contributor.author | Lupton, MK | |
dc.contributor.author | Troakes, C | |
dc.contributor.author | Lunnon, K | |
dc.contributor.author | Al-Sarraj, S | |
dc.contributor.author | Brown, KS | |
dc.contributor.author | Medway, C | |
dc.contributor.author | Lord, J | |
dc.contributor.author | Turton, J | |
dc.contributor.author | ARUK Consortium | |
dc.contributor.author | Morgan, K | |
dc.contributor.author | Powell, JF | |
dc.contributor.author | Kauwe, JS | |
dc.contributor.author | Cruchaga, C | |
dc.contributor.author | Bras, J | |
dc.contributor.author | Goate, AM | |
dc.contributor.author | Singleton, AB | |
dc.contributor.author | Guerreiro, R | |
dc.contributor.author | Hardy, J | |
dc.date.accessioned | 2017-03-13T10:01:36Z | |
dc.date.issued | 2016-06-01 | |
dc.description.abstract | The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4<p-value<0.05), were found to be rare coding variants (0.009%<MAF<1.4%) with moderate to strong effect size (1.84<OR<Inf) that map to genes mainly involved in Aβ extracellular degradation (TTR, ACE), clearance (LRP1) and APP trafficking and recycling (SORL1). These results were partially replicated in the gene-based analysis (c-alpha and SKAT tests), that reports ECE1, LYZ and TTR as nominally associated to AD (1.7e-3 <p-value <0.05). In concert with previous studies, we suggest that 1) common coding variability in APP-Aβ genes is not a critical factor for AD development and 2) Aβ degradation and clearance, rather than Aβ production, may play a key role in the etiology of sporadic AD. | en_GB |
dc.description.sponsorship | This study was supported by the
Alzheimer's Research UK, the Medical Research
Council (MRC), the Wellcome Trust/MRC Joint Call in
Neurodegeneration Award (WT089698) to the UK
Parkinson's Disease Consortium (whose members
are from the University College London Institute of
Neurology, the University of Sheffield, and the MRC
Protein Phosphorylation Unit at the University of
Dundee), grants (P50 AG016574, U01 AG006786,
and R01 AG18023), the National Institute for Health
Research Biomedical Research Unit in Dementia at University College London Hospitals, University
College London; the Big Lottery (to Dr. Morgan); a
fellowship from Alzheimer's Research UK (to Dr.
Guerreiro); and the Intramural Research Programs of
the National Institute on Aging and the National
Institute of Neurological Disease and Stroke, National
Institutes of Health (Department of Health and Human
Services Project number, ZO1 AG000950-10). The
MRC London Neurodegenerative Diseases Brain
Bank and the Manchester Brain Bank from Brains for
Dementia Research are jointly funded from ARUK
and AS. Tissue samples were supplied by The
London Neurodegenerative Diseases Brain Bank,
which receives funding from the MRC and as part of
the Brains for Dementia Research programme, jointly
funded by Alzheimer’s Research UK and Alzheimer’s
Society. | en_GB |
dc.identifier.citation | Vol. 11, e0150079 | en_GB |
dc.identifier.doi | 10.1371/journal.pone.0150079 | |
dc.identifier.uri | http://hdl.handle.net/10871/26489 | |
dc.language.iso | en | en_GB |
dc.publisher | Public Library of Science | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/27249223 | en_GB |
dc.rights | This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. | en_GB |
dc.title | Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimer’s disease | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2017-03-13T10:01:36Z | |
dc.identifier.issn | 1932-6203 | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version of the article. Available on open access from the publisher via the DOI in this record. | en_GB |
dc.identifier.journal | PLoS One | en_GB |