Deep sequencing of the nicastrin gene in pooled DNA, the identification of genetic variants that affect risk of Alzheimer's disease

Lupton, Michelle K., Proitsi, Petroula, Danillidou, Makrina, Tsolaki, Magda, Hamilton, Gillian, Wroe, Richard, Pritchard, Megan, Lord, Kathryn, Martin, Belinda M., Kloszewska, Iwona, Soininen, Hilkka, Mecocci, Patrizia, Vellas, Bruno, Harold, Denise, Hollingworth, Paul, Lovestone, Simon and Powell, John F. 2011. Deep sequencing of the nicastrin gene in pooled DNA, the identification of genetic variants that affect risk of Alzheimer's disease. PLoS ONE 6 (2) , e17298. 10.1371/journal.pone.0017298

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Abstract

Nicastrin is an obligatory component of the γ-secretase; the enzyme complex that leads to the production of Aβ fragments critically central to the pathogenesis of Alzheimer's disease (AD). Analyses of the effects of common variation in this gene on risk for late onset AD have been inconclusive. We investigated the effect of rare variation in the coding regions of the Nicastrin gene in a cohort of AD patients and matched controls using an innovative pooling approach and next generation sequencing. Five SNPs were identified and validated by individual genotyping from 311 cases and 360 controls. Association analysis identified a non-synonymous rare SNP (N417Y) with a statistically higher frequency in cases compared to controls in the Greek population (OR 3.994, CI 1.105-14.439, p = 0.035). This finding warrants further investigation in a larger cohort and adds weight to the hypothesis that rare variation explains some of genetic heritability still to be identified in Alzheimer's disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	R Medicine > R Medicine (General)
Additional Information:	© 2011 Lupton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Publisher:	Public Library of Science
ISSN:	1932-6203
Date of First Compliant Deposit:	30 March 2016
Last Modified:	06 May 2023 03:48
URI:	https://orca.cardiff.ac.uk/id/eprint/80475

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