Skip to main content

Research Repository

Advanced Search

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.

Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease Thumbnail


Authors

C. Sassi

P. Ridge

M.A. Nalls

R. Gibbs

J. Ding

M.K. Lupton

C. Troakes

K. Lunnon

S. Al-Sarraj

K.S. Brown

C. Medway

J. Lord

Kevin Morgan

James Turton

J.F. Powell

J.S. Kauwe

C. Cruchaga

J. Bras

A.M. Goate

A. Singleton

Rita Guerreiro

J. Hardy



Abstract

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.

Citation

Sassi, C., Ridge, P., Nalls, M., Gibbs, R., Ding, J., Lupton, M., …Hardy, J. (in press). Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease. PLoS ONE, https://doi.org/10.1371/journal.pone.0150079

Journal Article Type Article
Acceptance Date Apr 22, 2016
Online Publication Date Jun 1, 2016
Deposit Date May 17, 2016
Publicly Available Date Mar 28, 2024
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1371/journal.pone.0150079
Keywords Alzheimer’s disease, APP-Aß metabolism, exome sequencing, genome sequencing
Public URL https://nottingham-repository.worktribe.com/output/783983
Publisher URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150079

Files







You might also like



Downloadable Citations