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; AR 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; 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; Peter P De Deyn; 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; Steven G Younkin; 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, AR 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, 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, Peter P De Deyn, 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, Steven G Younkin, Peter A Holmans, Michael O'Donovan, Michael J Owen, Julie Williams

Norwich Medical School

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

2213 Citations (Scopus)

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
Publication status	Published - 2009

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10.1038/ng.440

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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, AR., 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

Harold, Denise ; Abraham, Richard ; Hollingworth, Paul ; Sims, Rebecca ; Gerrish, Amy ; Hamshere, Marian L ; Pahwa, Jaspreet Singh ; Moskvina, Valentina ; Dowzell, Kimberley ; Williams, Amy ; Jones, Nicola ; Thomas, Charlene ; Stretton, Alexandra ; Morgan, AR ; Lovestone, Simon ; Powell, John ; Proitsi, Petroula ; Lupton, Michelle K ; Brayne, Carol ; Rubinsztein, David C ; Gill, Michael ; Lawlor, Brian ; Lynch, Aoibhinn ; Morgan, Kevin ; Brown, Kristelle S ; Passmore, Peter A ; Craig, David ; McGuinness, Bernadette ; Todd, Stephen ; Holmes, Clive ; Mann, David ; Smith, A David ; Love, Seth ; Kehoe, Patrick G ; Hardy, John ; Mead, Simon ; Fox, Nick ; Rossor, Martin ; Collinge, John ; Maier, Wolfgang ; Jessen, Frank ; Schürmann, Britta ; van den Bussche, Hendrik ; Heuser, Isabella ; Kornhuber, Johannes ; Wiltfang, Jens ; Dichgans, Martin ; Frölich, Lutz ; Hampel, Harald ; Hüll, Michael ; Rujescu, Dan ; Goate, Alison M ; Kauwe, John S K ; Cruchaga, Carlos ; Nowotny, Petra ; Morris, John C ; Mayo, Kevin ; Sleegers, Kristel ; Bettens, Karolien ; Engelborghs, Sebastiaan ; De Deyn, Peter P ; Van Broeckhoven, Christine ; Livingston, Gill ; Bass, Nicholas J ; Gurling, Hugh ; McQuillin, Andrew ; Gwilliam, Rhian ; Deloukas, Panagiotis ; Al-Chalabi, Ammar ; Shaw, Christopher E ; Tsolaki, Magda ; Singleton, Andrew B ; Guerreiro, Rita ; Mühleisen, Thomas W ; Nöthen, Markus M ; Moebus, Susanne ; Jöckel, Karl-Heinz ; Klopp, Norman ; Wichmann, H-Erich ; Carrasquillo, Minerva M ; Pankratz, V Shane ; Younkin, Steven G ; Holmans, Peter A ; O'Donovan, Michael ; Owen, Michael J ; Williams, Julie. / Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. In: Nature Genetics. 2009 ; Vol. 41, No. 10. pp. 1088-1093.

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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 AR Morgan 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 {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 {De Deyn}, {Peter P} 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 Karl-Heinz J{\"o}ckel and Norman Klopp and H-Erich Wichmann and Carrasquillo, {Minerva M} and Pankratz, {V Shane} and Younkin, {Steven G} and Holmans, {Peter A} and Michael O'Donovan and Owen, {Michael J} and Julie Williams",

year = "2009",

doi = "10.1038/ng.440",

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pages = "1088--1093",

journal = "Nature Genetics",

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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, 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, De Deyn, PP, 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, K-H, Klopp, N, Wichmann, H-E, Carrasquillo, MM, Pankratz, VS, Younkin, SG, 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

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. / Harold, Denise; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Hamshere, Marian L; Pahwa, Jaspreet Singh; Moskvina, Valentina; Dowzell, Kimberley; Williams, Amy; Jones, Nicola; Thomas, Charlene; Stretton, Alexandra; Morgan, AR; Lovestone, Simon; Powell, John; Proitsi, Petroula; Lupton, Michelle K; Brayne, Carol; Rubinsztein, David C; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Morgan, Kevin; Brown, Kristelle S; Passmore, Peter A; Craig, David; McGuinness, Bernadette; Todd, Stephen; Holmes, Clive; Mann, David; Smith, A David; Love, Seth; Kehoe, Patrick G; Hardy, John; Mead, Simon; Fox, Nick; Rossor, Martin; Collinge, John; Maier, Wolfgang; Jessen, Frank; Schürmann, Britta; van den Bussche, Hendrik; Heuser, Isabella; Kornhuber, Johannes; Wiltfang, Jens; Dichgans, Martin; Frölich, Lutz; Hampel, Harald; Hüll, Michael; Rujescu, Dan; Goate, Alison M; Kauwe, John S K; Cruchaga, Carlos; Nowotny, Petra; Morris, John C; Mayo, Kevin; Sleegers, Kristel; Bettens, Karolien; Engelborghs, Sebastiaan; De Deyn, Peter P; Van Broeckhoven, Christine; Livingston, Gill; Bass, Nicholas J; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panagiotis; Al-Chalabi, Ammar; Shaw, Christopher E; Tsolaki, Magda; Singleton, Andrew B; Guerreiro, Rita; Mühleisen, Thomas W; Nöthen, Markus M; Moebus, Susanne; Jöckel, Karl-Heinz; Klopp, Norman; Wichmann, H-Erich; Carrasquillo, Minerva M; Pankratz, V Shane; Younkin, Steven G; Holmans, Peter A; O'Donovan, Michael; Owen, Michael J; Williams, Julie.

In: Nature Genetics, Vol. 41, No. 10, 2009, p. 1088-1093.

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

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, AR

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 - 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 - De Deyn, Peter P

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 - Younkin, Steven G

AU - Holmans, Peter A

AU - O'Donovan, Michael

AU - Owen, Michael J

AU - Williams, Julie

PY - 2009

Y1 - 2009

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).

U2 - 10.1038/ng.440

DO - 10.1038/ng.440

M3 - Article

VL - 41

SP - 1088

EP - 1093

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 10

ER -