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 W Medway, Jenny Lord, James Turton, ARUK Consortium, John Hardy

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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
Number of pages14
JournalPLoS ONE
Volume11
Issue number6
DOIs
Publication statusPublished - 1 Jun 2016

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