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

D. Harold; R. Abraham; P. Hollingworth; R. Sims; A. Gerrish; M.L. Hamshere; J.S. Pahwa; V. Moskvina; K. Dowzell; A. Williams; N. Jones; C. Thomas; A. Stretton; A.R. Morgan; S. Lovestone; J. Powell; P. Proitsi; M.K. Lupton; C. Brayne; D.C. Rubinsztein; M. Gill; B. Lawlor; A. Lynch; K. Morgan; K.S. Brown; Peter A. Passmore; David Craig; Bernadette McGuinness; Stephen Todd; C. Holmes; D. Mann; A.D. Smith; S. Love; P.G. Kehoe; J. Hardy; S. Mead; N. Fox; M. Rossor; J. Collinge; W. Maier; F. Jessen; B. Schurmann; H. Van Den Bussche; I. Heuser; J. Kornhuber; J. Wiltfang; M. Dichgans; L. Frolich; H. Hampel; M. Hull; D. Rujescu; A.M. Goate; J.S.K. Kauwe; C. Cruchaga; P. Nowotny; J.C. Morris; K. Mayo; K. Sleegers; K. Bettens; S. Engelborghs; P.P. De Deyn; C. Van Broeckhoven; G. Livingston; N.J. Bass; H. Gurling; A. McQuillin; R. Gwilliam; P. Deloukas; A. Al-Chalabi; C.E. Shaw; M. Tsolaki; A.B. Singleton; R. Guerreiro; T.W. Muhleisen; M.M. Nothen; S. Moebus; K.H. Jockel; N. Klopp; H.E. Wichmann; M.M. Carrasquillo; V.S. Pankratz; S.G. Younkin; P.A. Holmans; M. O'Donovan; M.J. Owen; J. Williams

doi:10.1038/ng.440

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

D. Harold, R. Abraham, P. Hollingworth, R. Sims, A. Gerrish, M.L. Hamshere, J.S. Pahwa, V. Moskvina, K. Dowzell, A. Williams, N. Jones, C. Thomas, A. Stretton, A.R. Morgan, S. Lovestone, J. Powell, P. Proitsi, M.K. Lupton, C. Brayne, D.C. RubinszteinM. Gill, B. Lawlor, A. Lynch, K. Morgan, K.S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, C. Holmes, D. Mann, A.D. Smith, S. Love, P.G. Kehoe, J. Hardy, S. Mead, N. Fox, M. Rossor, J. Collinge, W. Maier, F. Jessen, B. Schurmann, H. Van Den Bussche, I. Heuser, J. Kornhuber, J. Wiltfang, M. Dichgans, L. Frolich, H. Hampel, M. Hull, D. Rujescu, A.M. Goate, J.S.K. Kauwe, C. Cruchaga, P. Nowotny, J.C. Morris, K. Mayo, K. Sleegers, K. Bettens, S. Engelborghs, P.P. De Deyn, C. Van Broeckhoven, G. Livingston, N.J. Bass, H. Gurling, A. McQuillin, R. Gwilliam, P. Deloukas, A. Al-Chalabi, C.E. Shaw, M. Tsolaki, A.B. Singleton, R. Guerreiro, T.W. Muhleisen, M.M. Nothen, S. Moebus, K.H. Jockel, N. Klopp, H.E. Wichmann, M.M. Carrasquillo, V.S. Pankratz, S.G. Younkin, P.A. Holmans, M. O'Donovan, M.J. Owen, J. 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
Early online date	06 Sept 2009
DOIs	https://doi.org/10.1038/ng.440
Publication status	Published - 02 Oct 2009

ASJC Scopus subject areas

Genetics

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Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's diseaseAccepted author manuscript, 423 KB

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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

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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).",

author = "D. Harold and R. Abraham and P. Hollingworth and R. Sims and A. Gerrish and M.L. Hamshere and J.S. Pahwa and V. Moskvina and K. Dowzell and A. Williams and N. Jones and C. Thomas and A. Stretton and A.R. Morgan and S. Lovestone and J. Powell and P. Proitsi and M.K. Lupton and C. Brayne and D.C. Rubinsztein and M. Gill and B. Lawlor and A. Lynch and K. Morgan and K.S. Brown and Passmore, {Peter A.} and David Craig and Bernadette McGuinness and Stephen Todd and C. Holmes and D. Mann and A.D. Smith and S. Love and P.G. Kehoe and J. Hardy and S. Mead and N. Fox and M. Rossor and J. Collinge and W. Maier and F. Jessen and B. Schurmann and {Van Den Bussche}, H. and I. Heuser and J. Kornhuber and J. Wiltfang and M. Dichgans and L. Frolich and H. Hampel and M. Hull and D. Rujescu and A.M. Goate and J.S.K. Kauwe and C. Cruchaga and P. Nowotny and J.C. Morris and K. Mayo and K. Sleegers and K. Bettens and S. Engelborghs and {De Deyn}, P.P. and {Van Broeckhoven}, C. and G. Livingston and N.J. Bass and H. Gurling and A. McQuillin and R. Gwilliam and P. Deloukas and A. Al-Chalabi and C.E. Shaw and M. Tsolaki and A.B. Singleton and R. Guerreiro and T.W. Muhleisen and M.M. Nothen and S. Moebus and K.H. Jockel and N. Klopp and H.E. Wichmann and M.M. Carrasquillo and V.S. Pankratz and S.G. Younkin and P.A. Holmans and M. O'Donovan and M.J. Owen and J. Williams",

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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, Schurmann, B, Van Den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frolich, L, Hampel, H, Hull, 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, Muhleisen, TW, Nothen, MM, Moebus, S, Jockel, KH, Klopp, N, Wichmann, HE, 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

TY - JOUR

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

AU - Harold, D.

AU - Abraham, R.

AU - Hollingworth, P.

AU - Sims, R.

AU - Gerrish, A.

AU - Hamshere, M.L.

AU - Pahwa, J.S.

AU - Moskvina, V.

AU - Dowzell, K.

AU - Williams, A.

AU - Jones, N.

AU - Thomas, C.

AU - Stretton, A.

AU - Morgan, A.R.

AU - Lovestone, S.

AU - Powell, J.

AU - Proitsi, P.

AU - Lupton, M.K.

AU - Brayne, C.

AU - Rubinsztein, D.C.

AU - Gill, M.

AU - Lawlor, B.

AU - Lynch, A.

AU - Morgan, K.

AU - Brown, K.S.

AU - Passmore, Peter A.

AU - Craig, David

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Holmes, C.

AU - Mann, D.

AU - Smith, A.D.

AU - Love, S.

AU - Kehoe, P.G.

AU - Hardy, J.

AU - Mead, S.

AU - Fox, N.

AU - Rossor, M.

AU - Collinge, J.

AU - Maier, W.

AU - Jessen, F.

AU - Schurmann, B.

AU - Van Den Bussche, H.

AU - Heuser, I.

AU - Kornhuber, J.

AU - Wiltfang, J.

AU - Dichgans, M.

AU - Frolich, L.

AU - Hampel, H.

AU - Hull, M.

AU - Rujescu, D.

AU - Goate, A.M.

AU - Kauwe, J.S.K.

AU - Cruchaga, C.

AU - Nowotny, P.

AU - Morris, J.C.

AU - Mayo, K.

AU - Sleegers, K.

AU - Bettens, K.

AU - Engelborghs, S.

AU - De Deyn, P.P.

AU - Van Broeckhoven, C.

AU - Livingston, G.

AU - Bass, N.J.

AU - Gurling, H.

AU - McQuillin, A.

AU - Gwilliam, R.

AU - Deloukas, P.

AU - Al-Chalabi, A.

AU - Shaw, C.E.

AU - Tsolaki, M.

AU - Singleton, A.B.

AU - Guerreiro, R.

AU - Muhleisen, T.W.

AU - Nothen, M.M.

AU - Moebus, S.

AU - Jockel, K.H.

AU - Klopp, N.

AU - Wichmann, H.E.

AU - Carrasquillo, M.M.

AU - Pankratz, V.S.

AU - Younkin, S.G.

AU - Holmans, P.A.

AU - O'Donovan, M.

AU - Owen, M.J.

AU - Williams, J.

PY - 2009/10/2

Y1 - 2009/10/2

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

C2 - 19786950

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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