Deep Sequencing of the Nicastrin Gene in Pooled DNA, the Identification of Genetic Variants That Affect Risk of Alzheimer's Disease

作者：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; Powell John F

来源：PLos One, 2011, 6(2): e17298.

DOI：10.1371/journal.pone.0017298

Nicastrin is an obligatory component of the c-secretase; the enzyme complex that leads to the production of Ab 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.

• 出版日期2011-2-25