Al-Sarraj, Safa

Brown, Kristelle S.

Ding, Jinhui

Gibbs, Raphael

Hardy, John

Lord, Jenny

Lunnon, Katie

Lupton, Michelle K.

Medway, Christopher W

Nalls, Michael A.

Ridge, Perry G.

Sassi, Celeste

Troakes, Claire

Turton, James

PLoS ONE

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&lt;p-value&lt;0.05), were found to be rare coding variants (0.009%&lt;MAF&lt;1.4%) with moderate to strong effect size (1.84&lt;OR&lt;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 &lt;p-value &lt;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.</p

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Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer’s Disease

https://research-information.bris.ac.uk/files/109400495/journal.pone.0150079.PDF

Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer’s Disease

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