Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease
The cerebral deposition of Aß42, a neurotoxic proteolitic derivate of amyloid precursor protein (APP), is a central event in Alzheimer’s disease (AD)(Amyloid hypothesis). Given the key role of APP-Aß metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aß degradation and c...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Public Library of Science
2016
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| Online Access: | https://eprints.nottingham.ac.uk/33347/ |
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| author | Sassi, C. Ridge, P. Nalls, M.A. Gibbs, R. Ding, J. Lupton, M.K. Troakes, C. Lunnon, K. Al-Sarraj, S. Brown, K.S. Medway, C. Lord, J. Morgan, Kevin Turton, James Powell, J.F. Kauwe, J.S. Cruchaga, C. Bras, J. Goate, A.M. Singleton, A. Guerreiro, Rita Hardy, J. |
| author_facet | Sassi, C. Ridge, P. Nalls, M.A. Gibbs, R. Ding, J. Lupton, M.K. Troakes, C. Lunnon, K. Al-Sarraj, S. Brown, K.S. Medway, C. Lord, J. Morgan, Kevin Turton, James Powell, J.F. Kauwe, J.S. Cruchaga, C. Bras, J. Goate, A.M. Singleton, A. Guerreiro, Rita Hardy, J. |
| author_sort | Sassi, C. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | The cerebral deposition of Aß42, a neurotoxic proteolitic derivate of amyloid precursor protein (APP), is a central event in Alzheimer’s disease (AD)(Amyloid hypothesis). Given the key role of APP-Aß metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aß 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 435 sporadic and mainly late-onset AD cases and 801 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, which were nominally significant, were found to be very rare coding variants (MAF 0.3%-0.8%) that map to genes involved in APP processing (MEP1B), trafficking and recycling (SORL1), Aß extracellular degradation (ACE) and clearance (LRP1). Moreover, four genes (ECE1, LYZ, TTR and MME) have been found as nominally associated to AD using c-alpha and SKAT tests. We suggest that Aβ degradation and clearance, rather than Aβ production, may play a crucial role in the etiology of sporadic AD. |
| first_indexed | 2025-11-14T19:18:56Z |
| format | Article |
| id | nottingham-33347 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:18:56Z |
| publishDate | 2016 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-333472020-05-04T17:45:22Z https://eprints.nottingham.ac.uk/33347/ Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease Sassi, C. Ridge, P. Nalls, M.A. Gibbs, R. Ding, J. Lupton, M.K. Troakes, C. Lunnon, K. Al-Sarraj, S. Brown, K.S. Medway, C. Lord, J. Morgan, Kevin Turton, James Powell, J.F. Kauwe, J.S. Cruchaga, C. Bras, J. Goate, A.M. Singleton, A. Guerreiro, Rita Hardy, J. The cerebral deposition of Aß42, a neurotoxic proteolitic derivate of amyloid precursor protein (APP), is a central event in Alzheimer’s disease (AD)(Amyloid hypothesis). Given the key role of APP-Aß metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aß 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 435 sporadic and mainly late-onset AD cases and 801 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, which were nominally significant, were found to be very rare coding variants (MAF 0.3%-0.8%) that map to genes involved in APP processing (MEP1B), trafficking and recycling (SORL1), Aß extracellular degradation (ACE) and clearance (LRP1). Moreover, four genes (ECE1, LYZ, TTR and MME) have been found as nominally associated to AD using c-alpha and SKAT tests. We suggest that Aβ degradation and clearance, rather than Aβ production, may play a crucial role in the etiology of sporadic AD. Public Library of Science 2016-04-22 Article PeerReviewed Sassi, C., Ridge, P., Nalls, M.A., Gibbs, R., Ding, J., Lupton, M.K., Troakes, C., Lunnon, K., Al-Sarraj, S., Brown, K.S., Medway, C., Lord, J., Morgan, Kevin, Turton, James, Powell, J.F., Kauwe, J.S., Cruchaga, C., Bras, J., Goate, A.M., Singleton, A., Guerreiro, Rita and Hardy, J. (2016) Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease. PLoS ONE . ISSN 1932-6203 (In Press) Alzheimer’s disease APP-Aß metabolism exome sequencing genome sequencing |
| spellingShingle | Alzheimer’s disease APP-Aß metabolism exome sequencing genome sequencing Sassi, C. Ridge, P. Nalls, M.A. Gibbs, R. Ding, J. Lupton, M.K. Troakes, C. Lunnon, K. Al-Sarraj, S. Brown, K.S. Medway, C. Lord, J. Morgan, Kevin Turton, James Powell, J.F. Kauwe, J.S. Cruchaga, C. Bras, J. Goate, A.M. Singleton, A. Guerreiro, Rita Hardy, J. Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease |
| title | Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease |
| title_full | Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease |
| title_fullStr | Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease |
| title_full_unstemmed | Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease |
| title_short | Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease |
| title_sort | influence of coding variability in app-aß metabolism genes in sporadic alzheimer's disease |
| topic | Alzheimer’s disease APP-Aß metabolism exome sequencing genome sequencing |
| url | https://eprints.nottingham.ac.uk/33347/ |