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

Michelle K. Lupton; Petroula Proitsi; Makrina Danillidou; Magda Tsolaki; Gillian Hamilton; Richard Wroe; Megan Pritchard; Kathryn Lord; Belinda M. Martin; Iwona Kloszewska; Hilkka Soininen; Patrizia Mecocci; Bruno Vellas; Denise Harold; Paul Hollingworth; Simon Lovestone; John F. Powell

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

Michelle K. Lupton, Petroula Proitsi, Makrina Danillidou, Magda Tsolaki, Gillian Hamilton, Richard Wroe, Megan Pritchard, Kathryn Lord, Belinda M. Martin, Iwona Kloszewska, Hilkka Soininen, Patrizia Mecocci, Bruno Vellas, Denise Harold, Paul Hollingworth, Simon Lovestone, John F. Powell

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	e17298
Journal	PL o S One
Volume	6
Issue number	2
Publication status	Published - 2011

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Lupton, M. K., Proitsi, P., Danillidou, M., Tsolaki, M., Hamilton, G., Wroe, R., Pritchard, M., Lord, K., Martin, B. M., Kloszewska, I., Soininen, H., Mecocci, P., Vellas, B., Harold, D., Hollingworth, P., Lovestone, S., & Powell, J. F. (2011). Deep Sequencing of the Nicastrin Gene in Pooled DNA, the Identification of Genetic Variants That Affect Risk of Alzheimer's Disease. PL o S One , 6(2), Article e17298.

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

abstract = "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.",

author = "Lupton, {Michelle K.} and Petroula Proitsi and Makrina Danillidou and Magda Tsolaki and Gillian Hamilton and Richard Wroe and Megan Pritchard and Kathryn Lord and Martin, {Belinda M.} and Iwona Kloszewska and Hilkka Soininen and Patrizia Mecocci and Bruno Vellas and Denise Harold and Paul Hollingworth and Simon Lovestone and Powell, {John F.}",

year = "2011",

language = "English",

volume = "6",

journal = "PL o S One ",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "2",

}

Lupton, MK, Proitsi, P, Danillidou, M, Tsolaki, M, Hamilton, G, Wroe, R, Pritchard, M , Lord, K , Martin, BM, Kloszewska, I, Soininen, H, Mecocci, P, Vellas, B, Harold, D, Hollingworth, P, Lovestone, S & Powell, JF 2011, 'Deep Sequencing of the Nicastrin Gene in Pooled DNA, the Identification of Genetic Variants That Affect Risk of Alzheimer's Disease', PL o S One , vol. 6, no. 2, e17298.

TY - JOUR

T1 - Deep Sequencing of the Nicastrin Gene in Pooled DNA, the Identification of Genetic Variants That Affect Risk of Alzheimer's Disease

AU - Lupton, Michelle K.

AU - Proitsi, Petroula

AU - Danillidou, Makrina

AU - Tsolaki, Magda

AU - Hamilton, Gillian

AU - Wroe, Richard

AU - Pritchard, Megan

AU - Lord, Kathryn

AU - Martin, Belinda M.

AU - Kloszewska, Iwona

AU - Soininen, Hilkka

AU - Mecocci, Patrizia

AU - Vellas, Bruno

AU - Harold, Denise

AU - Hollingworth, Paul

AU - Lovestone, Simon

AU - Powell, John F.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

M3 - Article

SN - 1932-6203

VL - 6

JO - PL o S One

JF - PL o S One

IS - 2

M1 - e17298

ER -

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

Abstract

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