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

Celeste Sassi, Perry G. Ridge, Michael A. Nalls, Raphael Gibbs, Jinhui Ding, Michelle K. Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S. Brown, Christopher Medway, Jenny Lord, James Turton, Kevin Morgan, John F. Powell, John S. Kauwe, Carlos Cruchaga, Jose Bras, Alison M. Goate, Andrew B. SingletonRita Guerreiro, John Hardy, Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinness, Stephen Todd, Reinhard Heun, Heike Kölsch, Patrick G. Kehoe, Nigel M. Hooper, Emma R.L.C. Vardy, David M. Mann, James Lowe, A. David Smith, Gordon Wilcock, Donald Warden, Clive Holmes

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26 Scopus citations

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 ADpathogenesis, we selected29 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 ADcases 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.

Original languageEnglish
Article numbere0150079
JournalPLoS ONE
Volume11
Issue number6
DOIs
StatePublished - Jun 2016

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