Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Denise Harold; Richard Abraham; Paul Hollingworth; Rebecca Sims; Amy Gerrish; Marian L. Hamshere; Jaspreet Singh Pahwa; Valentina Moskvina; 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; 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; Britta Schürmann; Reinhard Heun; 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; Kristel Sleegers; Karolien Bettens; Sebastiaan Engelborghs; Christine Van Broeckhoven; Gill Livingston; Nicholas J. Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; 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; Peter A. Holmans; Michael O'Donovan; Michael J. Owen; Julie Williams

doi:10.1038/ng.440

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Denise Harold, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Marian L. Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, 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. RubinszteinMichael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, 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, Britta Schürmann, Reinhard Heun, 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, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Christine Van Broeckhoven, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, 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, Peter A. Holmans, Michael O'Donovan, Michael J. Owen, Julie Williams

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Abstract

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10 157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10 8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).

Original language	English
Pages (from-to)	1088-1093
Number of pages	6
Journal	Nature Genetics
Volume	41
Issue number	10
DOIs	https://doi.org/10.1038/ng.440
State	Published - Oct 1 2009

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Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., Jones, N., Thomas, C., Stretton, A., Morgan, A. R., Lovestone, S., Powell, J., Proitsi, P., Lupton, M. K., Brayne, C., ... Williams, J. (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics, 41(10), 1088-1093. https://doi.org/10.1038/ng.440

@article{3b02500039d04f0dbd4a74461aae8bb8,

title = "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease",

abstract = "We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10 157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10 8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).",

author = "Denise Harold and Richard Abraham and Paul Hollingworth and Rebecca Sims and Amy Gerrish and Hamshere, {Marian L.} and Pahwa, {Jaspreet Singh} and Valentina Moskvina 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 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 Britta Sch{\"u}rmann and Reinhard Heun and {Van Den Bussche}, Hendrik 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 Kristel Sleegers and Karolien Bettens and Sebastiaan Engelborghs and {Van Broeckhoven}, Christine and Gill Livingston and Bass, {Nicholas J.} and Hugh Gurling and Andrew McQuillin and Rhian Gwilliam and Panagiotis Deloukas 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 Holmans, {Peter A.} and Michael O'Donovan and Owen, {Michael J.} and Julie Williams",

note = "Funding Information: We thank the individuals and families who took part in this research. Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC, UK), Alzheimer{\textquoteright}s Research Trust (ART) and the Welsh Assembly Government. ART supported sample collections at the Institute of Psychiatry, the South West Dementia Bank and the Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer{\textquoteright}s Society, Ulster Garden Villages, Northern Ireland Research and Development Office and the Royal College of Physicians–Dunhill Medical Trust. The MRC and Mercer{\textquoteright}s Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer{\textquoteright}s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the Oxford Project to Investigate Memory and Ageing (OPTIMA) group. A.A.-C. and C.E.S. thank the Motor Neurone Disease Association and MRC for support. D.C.R. is a Wellcome Trust Senior Clinical Research Fellow. Washington University was funded by US National Institutes of Health (NIH) grants, the Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer{\textquoteright}s Research Initiative. The Mayo GWAS was supported by NIH grants, the Robert and Clarice Smith and Abigail Van Buren AD Research Program, and the Palumbo Professorship in AD Research. Patient recruitment for the MRC Prion Unit/University College London Department of Neurodegenerative Disease collection was supported by the UCL Hospital/UCL Biomedical Centre. London and the South East Region (LASER)-AD was funded by Lundbeck. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The Kooperative gesundheitsforschung in der region Augsburg (KORA) F4 studies were financed by Helmholtz Zentrum M{\"u}nchen, the German Research Center for Environmental Health, BMBF, the German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (G. Schmidt, chairman) and BMBF. Coriell Cell Repositories is supported by the US National Institute of Neurological Disorders and Stroke and the Intramural Research Program (IRP) of the National Institute on Aging (NIA). Work on this sample was supported in part by the IRP of the NIA, National Institutes of Health, Department of Health and Human Services; Z01 AG000950-06. We acknowledge use of DNA from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust, which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the US National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Antwerp site was supported by the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, the Special Research Fund of the University of Antwerp, the Fund for Scientific Research-Flanders, the Foundation for Alzheimer Research and the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office. K.S. is a postdoctoral fellow and K.B. a PhD fellow (Fund for Scientific Research-Flanders). We thank R. Brown, J. Landers, D. Warden, D. Lehmann, N. Leigh, J. Uphill, J. Beck, T. Campbell, S. Klier, G. Adamson, J. Wyatt, M.L. Perez, T. Meitinger, P. Lichtner, G. Eckstein, N. Graff-Radford, R. Petersen, D. Dickson, G. Fischer, H. Bickel, H. Jahn, H. Kaduszkiewicz, C. Luckhaus, S. Riedel-Heller, S. Wolf, S. Weyerer, the Helmholtz Zentrum M{\"u}nchen genotyping staff, E. Reiman, TGEN and the NIMH AD Genetics Initiative. We thank Advanced Research Computing @Cardiff (ARCCA), which facilitated data analysis.",

year = "2009",

month = oct,

day = "1",

doi = "10.1038/ng.440",

language = "English",

volume = "41",

pages = "1088--1093",

journal = "Nature Genetics",

issn = "1061-4036",

number = "10",

}

Harold, D, Abraham, R, Hollingworth, P, Sims, R, Gerrish, A, Hamshere, ML, Pahwa, JS, Moskvina, V, 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, Holmes, C, Mann, D, Smith, AD, Love, S, Kehoe, PG, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Schürmann, B, Heun, R, Van Den Bussche, H, 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, Sleegers, K, Bettens, K, Engelborghs, S, Van Broeckhoven, C, Livingston, G, Bass, NJ, Gurling, H, McQuillin, A, Gwilliam, R, Deloukas, P, 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, Holmans, PA, O'Donovan, M, Owen, MJ & Williams, J 2009, 'Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease', Nature Genetics, vol. 41, no. 10, pp. 1088-1093. https://doi.org/10.1038/ng.440

TY - JOUR

T1 - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

AU - Harold, Denise

AU - Abraham, Richard

AU - Hollingworth, Paul

AU - Sims, Rebecca

AU - Gerrish, Amy

AU - Hamshere, Marian L.

AU - Pahwa, Jaspreet Singh

AU - Moskvina, Valentina

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 - 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 - Schürmann, Britta

AU - Heun, Reinhard

AU - Van Den Bussche, Hendrik

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 - Sleegers, Kristel

AU - Bettens, Karolien

AU - Engelborghs, Sebastiaan

AU - Van Broeckhoven, Christine

AU - Livingston, Gill

AU - Bass, Nicholas J.

AU - Gurling, Hugh

AU - McQuillin, Andrew

AU - Gwilliam, Rhian

AU - Deloukas, Panagiotis

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 - Holmans, Peter A.

AU - O'Donovan, Michael

AU - Owen, Michael J.

AU - Williams, Julie

N1 - Funding Information: We thank the individuals and families who took part in this research. Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC, UK), Alzheimer’s Research Trust (ART) and the Welsh Assembly Government. ART supported sample collections at the Institute of Psychiatry, the South West Dementia Bank and the Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer’s Society, Ulster Garden Villages, Northern Ireland Research and Development Office and the Royal College of Physicians–Dunhill Medical Trust. The MRC and Mercer’s Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer’s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the Oxford Project to Investigate Memory and Ageing (OPTIMA) group. A.A.-C. and C.E.S. thank the Motor Neurone Disease Association and MRC for support. D.C.R. is a Wellcome Trust Senior Clinical Research Fellow. Washington University was funded by US National Institutes of Health (NIH) grants, the Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer’s Research Initiative. The Mayo GWAS was supported by NIH grants, the Robert and Clarice Smith and Abigail Van Buren AD Research Program, and the Palumbo Professorship in AD Research. Patient recruitment for the MRC Prion Unit/University College London Department of Neurodegenerative Disease collection was supported by the UCL Hospital/UCL Biomedical Centre. London and the South East Region (LASER)-AD was funded by Lundbeck. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The Kooperative gesundheitsforschung in der region Augsburg (KORA) F4 studies were financed by Helmholtz Zentrum München, the German Research Center for Environmental Health, BMBF, the German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (G. Schmidt, chairman) and BMBF. Coriell Cell Repositories is supported by the US National Institute of Neurological Disorders and Stroke and the Intramural Research Program (IRP) of the National Institute on Aging (NIA). Work on this sample was supported in part by the IRP of the NIA, National Institutes of Health, Department of Health and Human Services; Z01 AG000950-06. We acknowledge use of DNA from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust, which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the US National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Antwerp site was supported by the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, the Special Research Fund of the University of Antwerp, the Fund for Scientific Research-Flanders, the Foundation for Alzheimer Research and the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office. K.S. is a postdoctoral fellow and K.B. a PhD fellow (Fund for Scientific Research-Flanders). We thank R. Brown, J. Landers, D. Warden, D. Lehmann, N. Leigh, J. Uphill, J. Beck, T. Campbell, S. Klier, G. Adamson, J. Wyatt, M.L. Perez, T. Meitinger, P. Lichtner, G. Eckstein, N. Graff-Radford, R. Petersen, D. Dickson, G. Fischer, H. Bickel, H. Jahn, H. Kaduszkiewicz, C. Luckhaus, S. Riedel-Heller, S. Wolf, S. Weyerer, the Helmholtz Zentrum München genotyping staff, E. Reiman, TGEN and the NIMH AD Genetics Initiative. We thank Advanced Research Computing @Cardiff (ARCCA), which facilitated data analysis.

PY - 2009/10/1

Y1 - 2009/10/1

N2 - We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10 157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10 8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).

AB - We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10 157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10 8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).

UR - http://www.scopus.com/inward/record.url?scp=70349558522&partnerID=8YFLogxK

U2 - 10.1038/ng.440

DO - 10.1038/ng.440

M3 - Article

C2 - 19734902

AN - SCOPUS:70349558522

SN - 1061-4036

VL - 41

SP - 1088

EP - 1093

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

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