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 Medway; Jenny Lord; James Turton; Kevin Morgan; John F. Powell; John S. Kauwe; Carlos Cruchaga; Jose Bras; Alison M. Goate; Andrew B. Singleton; Rita Guerreiro; John Hardy; Peter Passmore; David Craig; Janet Johnston; Bernadette McGuinness; Stephen Todd; Reinhard Heun; Heike Kölsch; Patrick G. Kehoe; Nigel M. Hooper; Emma R L C Vardy; David M. Mann; James Lowe; A. David Smith; Gordon Wilcock; Donald Warden; Clive Holmes

doi:10.1371/journal.pone.0150079

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 Medway, Jenny Lord, James Turton, Kevin Morgan, John F. Powell, John S. Kauwe, Carlos Cruchaga, Jose Bras, Alison M. Goate, Andrew B. SingletonRita Guerreiro, John Hardy, Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinness, Stephen Todd, Reinhard Heun, Heike Kölsch, Patrick G. Kehoe, Nigel M. Hooper, Emma R L C Vardy, David M. Mann, James Lowe, A. David Smith, Gordon Wilcock, Donald Warden, Clive Holmes

Basic and Clinical Neuroscience

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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-⁴-3

Original language	English
Article number	e0150079
Journal	PL o S One
Volume	11
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0150079
Publication status	Published - 1 Jun 2016

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10.1371/journal.pone.0150079Licence: CC BY

Influence of Coding Variability_SASSI_Accepted 9Feb2016_GOLD VoRFinal published version, 196 KBLicence: CC BY

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Sassi, C., Ridge, P. G., Nalls, M. A., Gibbs, R., Ding, J., Lupton, M. K., Troakes, C., Lunnon, K., Al-Sarraj, S., Brown, K. S., Medway, C., Lord, J., Turton, J., Morgan, K., Powell, J. F., Kauwe, J. S., Cruchaga, C., Bras, J., Goate, A. M., ... Holmes, C. (2016). Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimer's disease. PL o S One , 11(6), Article e0150079. https://doi.org/10.1371/journal.pone.0150079

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title = "Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimer's disease",

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-4-3 ",

author = "Celeste Sassi and Ridge, {Perry G.} and Nalls, {Michael A.} and Raphael Gibbs and Jinhui Ding and Lupton, {Michelle K.} and Claire Troakes and Katie Lunnon and Safa Al-Sarraj and Brown, {Kristelle S.} and Christopher Medway and Jenny Lord and James Turton and Kevin Morgan and Powell, {John F.} and Kauwe, {John S.} and Carlos Cruchaga and Jose Bras and Goate, {Alison M.} and Singleton, {Andrew B.} and Rita Guerreiro and John Hardy and Peter Passmore and David Craig and Janet Johnston and Bernadette McGuinness and Stephen Todd and Reinhard Heun and Heike K{\"o}lsch and Kehoe, {Patrick G.} and Hooper, {Nigel M.} and Vardy, {Emma R L C} and Mann, {David M.} and James Lowe and {David Smith}, A. and Gordon Wilcock and Donald Warden and Clive Holmes",

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Sassi, C, Ridge, PG, Nalls, MA, Gibbs, R, Ding, J, Lupton, MK , Troakes, C , Lunnon, K , Al-Sarraj, S, Brown, KS, Medway, C, Lord, J, Turton, J, Morgan, K, Powell, JF, Kauwe, JS, Cruchaga, C, Bras, J, Goate, AM, Singleton, AB, Guerreiro, R, Hardy, J, Passmore, P, Craig, D, Johnston, J, McGuinness, B, Todd, S, Heun, R, Kölsch, H, Kehoe, PG, Hooper, NM, Vardy, ERLC, Mann, DM, Lowe, J, David Smith, A, Wilcock, G, Warden, D & Holmes, C 2016, 'Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimer's disease', PL o S One , vol. 11, no. 6, e0150079. https://doi.org/10.1371/journal.pone.0150079

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T1 - Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimer's disease

AU - Sassi, Celeste

AU - Ridge, Perry G.

AU - Nalls, Michael A.

AU - Gibbs, Raphael

AU - Ding, Jinhui

AU - Lupton, Michelle K.

AU - Troakes, Claire

AU - Lunnon, Katie

AU - Al-Sarraj, Safa

AU - Brown, Kristelle S.

AU - Medway, Christopher

AU - Lord, Jenny

AU - Turton, James

AU - Morgan, Kevin

AU - Powell, John F.

AU - Kauwe, John S.

AU - Cruchaga, Carlos

AU - Bras, Jose

AU - Goate, Alison M.

AU - Singleton, Andrew B.

AU - Guerreiro, Rita

AU - Hardy, John

AU - Passmore, Peter

AU - Craig, David

AU - Johnston, Janet

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Heun, Reinhard

AU - Kölsch, Heike

AU - Kehoe, Patrick G.

AU - Hooper, Nigel M.

AU - Vardy, Emma R L C

AU - Mann, David M.

AU - Lowe, James

AU - David Smith, A.

AU - Wilcock, Gordon

AU - Warden, Donald

AU - Holmes, Clive

PY - 2016/6/1

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AB - 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-4-3

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DO - 10.1371/journal.pone.0150079

M3 - Article

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VL - 11

JO - PL o S One

JF - PL o S One

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ER -

Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimer's disease

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