The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease

Amy Gerrish; Giancarlo Russo; Alexander Richards; Valentina Moskvina; Dobril Ivanov; Denise Harold; Rebecca Sims; Richard Abraham; Paul Hollingworth; Jade Chapman; Marian Hamshere; Jaspreet Singh Pahwa; Kimberley Dowzell; Amy Williams; Nicola Jones; Charlene Thomas; Alexandra Stretton; Angharad R. Morgan; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K. Lupton; Carol Brayne; David C. Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kevin Morgan; Kristelle S. Brown; Peter A. Passmore; David Craig; Bernadette McGuinness; Stephen Todd; Janet A. Johnston; Clive Holmes; David Mann; A. David Smith; Seth Love; Patrick G. Kehoe; John Hardy; Simon Mead; Nick Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Heike Kölsch; Reinhard Heun; Britta Schürmann; Hendrik Van Den Bussche; Isabella Heuser; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Frölich; Harald Hampel; Michael Hüll; Dan Rujescu; Alison M. Goate; John S K Kauwe; Carlos Cruchaga; Petra Nowotny; John C. Morris; Kevin Mayo; Gill Livingston; Nicholas J. Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; Gail Davies; Sarah E. Harris; John M. Starr; Ian J. Deary; Ammar Al-Chalabi; Christopher E. Shaw; Magda Tsolaki; Andrew B. Singleton; Rita Guerreiro; Thomas W. Mühleisen; Markus M. Nöthen; Susanne Moebus; Karl Heinz Jöckel; Norman Klopp; H. Erich Wichmann; Minerva M. Carrasquillo; V. Shane Pankratz; Steven G. Younkin; Lesley Jones; Peter A. Holmans; Michael C. O'Donovan; Michael J. Owen; Julie Williams

doi:10.3233/JAD-2011-110824

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease

Amy Gerrish, Giancarlo Russo, Alexander Richards, Valentina Moskvina, Dobril Ivanov, Denise Harold, Rebecca Sims, Richard Abraham, Paul Hollingworth, Jade Chapman, Marian Hamshere, Jaspreet Singh Pahwa, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John PowellPetroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Janet A. Johnston, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, John Hardy, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Heike Kölsch, Reinhard Heun, Britta Schürmann, Hendrik Van Den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison M. Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Gail Davies, Sarah E. Harris, John M. Starr, Ian J. Deary, Ammar Al-Chalabi, Christopher E. Shaw, Magda Tsolaki, Andrew B. Singleton, Rita Guerreiro, Thomas W. Mühleisen, Markus M. Nöthen, Susanne Moebus, Karl Heinz Jöckel, Norman Klopp, H. Erich Wichmann, Minerva M. Carrasquillo, V. Shane Pankratz, Steven G. Younkin, Lesley Jones, Peter A. Holmans, Michael C. O'Donovan, Michael J. Owen, Julie Williams

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

Abstract

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. © 2012 - IOS Press and the authors. All rights reserved.

Original language	English
Pages (from-to)	377-387
Number of pages	10
Journal	Journal of Alzheimer's Disease
Volume	28
Issue number	2
DOIs	https://doi.org/10.3233/JAD-2011-110824
Publication status	Published - 2012

Keywords

Alzheimer's disease
amyloid-β protein precursor
genetics
human
MAPT protein
PSEN1 protein
PSEN2 protein

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10.3233/JAD-2011-110824

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Gerrish, A., Russo, G., Richards, A., Moskvina, V., Ivanov, D., Harold, D., Sims, R., Abraham, R., Hollingworth, P., Chapman, J., Hamshere, M., Pahwa, J. S., Dowzell, K., Williams, A., Jones, N., Thomas, C., Stretton, A., Morgan, A. R., Lovestone, S., ... Williams, J. (2012). The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease. Journal of Alzheimer's Disease, 28(2), 377-387. https://doi.org/10.3233/JAD-2011-110824

@article{a5192da45e1e46bb96c4a0fbddecb858,

title = "The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease",

abstract = "Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. {\textcopyright} 2012 - IOS Press and the authors. All rights reserved.",

keywords = "Alzheimer's disease, amyloid-β protein precursor, genetics, human, MAPT protein, PSEN1 protein, PSEN2 protein",

author = "Amy Gerrish and Giancarlo Russo and Alexander Richards and Valentina Moskvina and Dobril Ivanov and Denise Harold and Rebecca Sims and Richard Abraham and Paul Hollingworth and Jade Chapman and Marian Hamshere and Pahwa, {Jaspreet Singh} and Kimberley Dowzell and Amy Williams and Nicola Jones and Charlene Thomas and Alexandra Stretton and Morgan, {Angharad R.} and Simon Lovestone and John Powell and Petroula Proitsi and Lupton, {Michelle K.} and Carol Brayne and Rubinsztein, {David C.} and Michael Gill and Brian Lawlor and Aoibhinn Lynch and Kevin Morgan and Brown, {Kristelle S.} and Passmore, {Peter A.} and David Craig and Bernadette McGuinness and Stephen Todd and Johnston, {Janet A.} and Clive Holmes and David Mann and Smith, {A. David} and Seth Love and Kehoe, {Patrick G.} and John Hardy and Simon Mead and Nick Fox and Martin Rossor and John Collinge and Wolfgang Maier and Frank Jessen and Heike K{\"o}lsch and Reinhard Heun and Britta Sch{\"u}rmann and Bussche, {Hendrik Van Den} and Isabella Heuser and Johannes Kornhuber and Jens Wiltfang and Martin Dichgans and Lutz Fr{\"o}lich and Harald Hampel and Michael H{\"u}ll and Dan Rujescu and Goate, {Alison M.} and Kauwe, {John S K} and Carlos Cruchaga and Petra Nowotny and Morris, {John C.} and Kevin Mayo and Gill Livingston and Bass, {Nicholas J.} and Hugh Gurling and Andrew McQuillin and Rhian Gwilliam and Panagiotis Deloukas and Gail Davies and Harris, {Sarah E.} and Starr, {John M.} and Deary, {Ian J.} and Ammar Al-Chalabi and Shaw, {Christopher E.} and Magda Tsolaki and Singleton, {Andrew B.} and Rita Guerreiro and M{\"u}hleisen, {Thomas W.} and N{\"o}then, {Markus M.} and Susanne Moebus and J{\"o}ckel, {Karl Heinz} and Norman Klopp and Wichmann, {H. Erich} and Carrasquillo, {Minerva M.} and Pankratz, {V. Shane} and Younkin, {Steven G.} and Lesley Jones and Holmans, {Peter A.} and O'Donovan, {Michael C.} and Owen, {Michael J.} and Julie Williams",

year = "2012",

doi = "10.3233/JAD-2011-110824",

language = "English",

volume = "28",

pages = "377--387",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "2",

}

Gerrish, A, Russo, G, Richards, A, Moskvina, V, Ivanov, D, Harold, D, Sims, R, Abraham, R, Hollingworth, P, Chapman, J, Hamshere, M, Pahwa, JS, Dowzell, K, Williams, A, Jones, N, Thomas, C, Stretton, A, Morgan, AR, Lovestone, S, Powell, J, Proitsi, P, Lupton, MK, Brayne, C, Rubinsztein, DC, Gill, M, Lawlor, B, Lynch, A, Morgan, K, Brown, KS, Passmore, PA, Craig, D, McGuinness, B, Todd, S, Johnston, JA, Holmes, C, Mann, D, Smith, AD, Love, S, Kehoe, PG, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Kölsch, H, Heun, R, Schürmann, B, Bussche, HVD, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Hüll, M, Rujescu, D, Goate, AM, Kauwe, JSK, Cruchaga, C, Nowotny, P, Morris, JC, Mayo, K, Livingston, G, Bass, NJ, Gurling, H, McQuillin, A, Gwilliam, R, Deloukas, P, Davies, G, Harris, SE, Starr, JM, Deary, IJ, Al-Chalabi, A, Shaw, CE, Tsolaki, M, Singleton, AB, Guerreiro, R, Mühleisen, TW, Nöthen, MM, Moebus, S, Jöckel, KH, Klopp, N, Wichmann, HE, Carrasquillo, MM, Pankratz, VS, Younkin, SG, Jones, L, Holmans, PA, O'Donovan, MC, Owen, MJ & Williams, J 2012, 'The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease', Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 377-387. https://doi.org/10.3233/JAD-2011-110824

TY - JOUR

T1 - The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease

AU - Gerrish, Amy

AU - Russo, Giancarlo

AU - Richards, Alexander

AU - Moskvina, Valentina

AU - Ivanov, Dobril

AU - Harold, Denise

AU - Sims, Rebecca

AU - Abraham, Richard

AU - Hollingworth, Paul

AU - Chapman, Jade

AU - Hamshere, Marian

AU - Pahwa, Jaspreet Singh

AU - Dowzell, Kimberley

AU - Williams, Amy

AU - Jones, Nicola

AU - Thomas, Charlene

AU - Stretton, Alexandra

AU - Morgan, Angharad R.

AU - Lovestone, Simon

AU - Powell, John

AU - Proitsi, Petroula

AU - Lupton, Michelle K.

AU - Brayne, Carol

AU - Rubinsztein, David C.

AU - Gill, Michael

AU - Lawlor, Brian

AU - Lynch, Aoibhinn

AU - Morgan, Kevin

AU - Brown, Kristelle S.

AU - Passmore, Peter A.

AU - Craig, David

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Johnston, Janet A.

AU - Holmes, Clive

AU - Mann, David

AU - Smith, A. David

AU - Love, Seth

AU - Kehoe, Patrick G.

AU - Hardy, John

AU - Mead, Simon

AU - Fox, Nick

AU - Rossor, Martin

AU - Collinge, John

AU - Maier, Wolfgang

AU - Jessen, Frank

AU - Kölsch, Heike

AU - Heun, Reinhard

AU - Schürmann, Britta

AU - Bussche, Hendrik Van Den

AU - Heuser, Isabella

AU - Kornhuber, Johannes

AU - Wiltfang, Jens

AU - Dichgans, Martin

AU - Frölich, Lutz

AU - Hampel, Harald

AU - Hüll, Michael

AU - Rujescu, Dan

AU - Goate, Alison M.

AU - Kauwe, John S K

AU - Cruchaga, Carlos

AU - Nowotny, Petra

AU - Morris, John C.

AU - Mayo, Kevin

AU - Livingston, Gill

AU - Bass, Nicholas J.

AU - Gurling, Hugh

AU - McQuillin, Andrew

AU - Gwilliam, Rhian

AU - Deloukas, Panagiotis

AU - Davies, Gail

AU - Harris, Sarah E.

AU - Starr, John M.

AU - Deary, Ian J.

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E.

AU - Tsolaki, Magda

AU - Singleton, Andrew B.

AU - Guerreiro, Rita

AU - Mühleisen, Thomas W.

AU - Nöthen, Markus M.

AU - Moebus, Susanne

AU - Jöckel, Karl Heinz

AU - Klopp, Norman

AU - Wichmann, H. Erich

AU - Carrasquillo, Minerva M.

AU - Pankratz, V. Shane

AU - Younkin, Steven G.

AU - Jones, Lesley

AU - Holmans, Peter A.

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Williams, Julie

PY - 2012

Y1 - 2012

N2 - Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. © 2012 - IOS Press and the authors. All rights reserved.

AB - Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. © 2012 - IOS Press and the authors. All rights reserved.

KW - Alzheimer's disease

KW - amyloid-β protein precursor

KW - genetics

KW - human

KW - MAPT protein

KW - PSEN1 protein

KW - PSEN2 protein

U2 - 10.3233/JAD-2011-110824

DO - 10.3233/JAD-2011-110824

M3 - Article

C2 - 22027014

SN - 1387-2877

VL - 28

SP - 377

EP - 387

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 2

ER -

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease

Abstract

Keywords

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