Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

P Hollingworth; R Sims; A Gerrish; D Harold; R Abraham; ML Hamshere; JS Pahwa; V Moskvina; K Dowzell; N Jones; A Stretton; A Richards; D Ivanov; C Widdowson; J Chapman; S Lovestone; J Powell; P Proitsi; MK Lupton; C Brayne; DC Rubinsztein; M Gill; B Lawlor; A Lynch; K Morgan; KS Brown; PA Passmore; D Craig; B McGuiness; S Todd; C Holmes; D Mann; AD Smith; S Love; PG Kehoe; J Hardy; S Mead; N Fox; M Rossor; J Collinge; W Maier; F Jessen; B Schürmann; H van den Bussche; I Heuser; J Kornhuber; J Wiltfang; M Dichgans; L Frölich; H Hampel; M Hüll; J Gallacher; D Rujescu; I Giegling; AM Goate; JSK Kauwe; C Cruchaga; P Nowotny; JC Morris; K Mayo; K Sleegers; K Bettens; S Engelborghs; PP De Deyn; C Van Broeckhoven; G Livingston; NJ Bass; H Gurling; A McQuillin; A Gwilliam; P Deloukas; A Al-Chalabi; CE Shaw; M Tsolaki; AB Singleton; R Guerreiro; TW Mühleisen; MM Nöthen; S Moebus; KH Jöckel; N Klopp; HE Wichmann; MM Carrasquillo; V Shane Pankratz; SG Younkin; Initiative The Alzheimer's Disease Neuroimaging; L Jones; PA Holmans; M O'Donovan; MJ Owen; J Williams

doi:10.1038/ng.803

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

P Hollingworth, R Sims, A Gerrish, D Harold, R Abraham, ML Hamshere, JS Pahwa, V Moskvina, K Dowzell, N Jones, A Stretton, A Richards, D Ivanov, C Widdowson, J Chapman, S Lovestone, J Powell, P Proitsi, MK Lupton, C BrayneDC Rubinsztein, M Gill, B Lawlor, A Lynch, K Morgan, KS Brown, PA Passmore, D Craig, B McGuiness, S Todd, C Holmes, D Mann, AD Smith, S Love, PG Kehoe, J Hardy, S Mead, N Fox, M Rossor, J Collinge, W Maier, F Jessen, B Schürmann, H van den Bussche, I Heuser, J Kornhuber, J Wiltfang, M Dichgans, L Frölich, H Hampel, M Hüll, J Gallacher, D Rujescu, I Giegling, AM Goate, JSK Kauwe, C Cruchaga, P Nowotny, JC Morris, K Mayo, K Sleegers, K Bettens, S Engelborghs, PP De Deyn, C Van Broeckhoven, G Livingston, NJ Bass, H Gurling, A McQuillin, A Gwilliam, P Deloukas, A Al-Chalabi, CE Shaw, M Tsolaki, AB Singleton, R Guerreiro, TW Mühleisen, MM Nöthen, S Moebus, KH Jöckel, N Klopp, HE Wichmann, MM Carrasquillo, V Shane Pankratz, SG Younkin, Initiative The Alzheimer's Disease Neuroimaging, L Jones, PA Holmans, M O'Donovan, MJ Owen, J Williams

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Abstract

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

Translated title of the contribution	Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease
Original language	English
Pages (from-to)	429 - 435
Number of pages	7
Journal	Nature Genetics
Volume	43 (5)
Issue number	5
DOIs	https://doi.org/10.1038/ng.803
Publication status	Published - May 2012

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Hollingworth, P., Sims, R., Gerrish, A., Harold, D., Abraham, R., Hamshere, ML., Pahwa, JS., Moskvina, V., Dowzell, K., Jones, N., Stretton, A., Richards, A., Ivanov, D., Widdowson, C., Chapman, J., Lovestone, S., Powell, J., Proitsi, P., Lupton, MK., ... Williams, J. (2012). Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genetics, 43 (5)(5), 429 - 435. https://doi.org/10.1038/ng.803

@article{4445f5fb9032456586065d471bb6673f,

title = "Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease",

abstract = "We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).",

author = "P Hollingworth and R Sims and A Gerrish and D Harold and R Abraham and ML Hamshere and JS Pahwa and V Moskvina and K Dowzell and N Jones and A Stretton and A Richards and D Ivanov and C Widdowson and J Chapman and S Lovestone and J Powell and P Proitsi and MK Lupton and C Brayne and DC Rubinsztein and M Gill and B Lawlor and A Lynch and K Morgan and KS Brown and PA Passmore and D Craig and B McGuiness and S Todd and C Holmes and D Mann and AD Smith and S Love and PG Kehoe and J Hardy and S Mead and N Fox and M Rossor and J Collinge and W Maier and F Jessen and B Sch{\"u}rmann and {van den Bussche}, H and I Heuser and J Kornhuber and J Wiltfang and M Dichgans and L Fr{\"o}lich and H Hampel and M H{\"u}ll and J Gallacher and D Rujescu and I Giegling and AM Goate and JSK Kauwe and C Cruchaga and P Nowotny and JC Morris and K Mayo and K Sleegers and K Bettens and S Engelborghs and {De Deyn}, PP and {Van Broeckhoven}, C and G Livingston and NJ Bass and H Gurling and A McQuillin and A Gwilliam and P Deloukas and A Al-Chalabi and CE Shaw and M Tsolaki and AB Singleton and R Guerreiro and TW M{\"u}hleisen and MM N{\"o}then and S Moebus and KH J{\"o}ckel and N Klopp and HE Wichmann and MM Carrasquillo and {Shane Pankratz}, V and SG Younkin and {The Alzheimer's Disease Neuroimaging}, Initiative and L Jones and PA Holmans and M O'Donovan and MJ Owen and J Williams",

year = "2012",

month = may,

doi = "10.1038/ng.803",

language = "English",

volume = "43 (5)",

pages = "429 -- 435",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "5",

}

Hollingworth, P, Sims, R, Gerrish, A, Harold, D, Abraham, R, Hamshere, ML, Pahwa, JS, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, 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, McGuiness, 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, Gallacher, J, Rujescu, D, Giegling, I, 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, A, 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, Shane Pankratz, V, Younkin, SG, The Alzheimer's Disease Neuroimaging, I, Jones, L, Holmans, PA, O'Donovan, M, Owen, MJ & Williams, J 2012, 'Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease', Nature Genetics, vol. 43 (5), no. 5, pp. 429 - 435. https://doi.org/10.1038/ng.803

TY - JOUR

T1 - Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

AU - Hollingworth, P

AU - Sims, R

AU - Gerrish, A

AU - Harold, D

AU - Abraham, R

AU - Hamshere, ML

AU - Pahwa, JS

AU - Moskvina, V

AU - Dowzell, K

AU - Jones, N

AU - Stretton, A

AU - Richards, A

AU - Ivanov, D

AU - Widdowson, C

AU - Chapman, J

AU - Lovestone, S

AU - Powell, J

AU - Proitsi, P

AU - Lupton, MK

AU - Brayne, C

AU - Rubinsztein, DC

AU - Gill, M

AU - Lawlor, B

AU - Lynch, A

AU - Morgan, K

AU - Brown, KS

AU - Passmore, PA

AU - Craig, D

AU - McGuiness, B

AU - Todd, S

AU - Holmes, C

AU - Mann, D

AU - Smith, AD

AU - Love, S

AU - Kehoe, PG

AU - Hardy, J

AU - Mead, S

AU - Fox, N

AU - Rossor, M

AU - Collinge, J

AU - Maier, W

AU - Jessen, F

AU - Schürmann, B

AU - van den Bussche, H

AU - Heuser, I

AU - Kornhuber, J

AU - Wiltfang, J

AU - Dichgans, M

AU - Frölich, L

AU - Hampel, H

AU - Hüll, M

AU - Gallacher, J

AU - Rujescu, D

AU - Giegling, I

AU - Goate, AM

AU - Kauwe, JSK

AU - Cruchaga, C

AU - Nowotny, P

AU - Morris, JC

AU - Mayo, K

AU - Sleegers, K

AU - Bettens, K

AU - Engelborghs, S

AU - De Deyn, PP

AU - Van Broeckhoven, C

AU - Livingston, G

AU - Bass, NJ

AU - Gurling, H

AU - McQuillin, A

AU - Gwilliam, A

AU - Deloukas, P

AU - Al-Chalabi, A

AU - Shaw, CE

AU - Tsolaki, M

AU - Singleton, AB

AU - Guerreiro, R

AU - Mühleisen, TW

AU - Nöthen, MM

AU - Moebus, S

AU - Jöckel, KH

AU - Klopp, N

AU - Wichmann, HE

AU - Carrasquillo, MM

AU - Shane Pankratz, V

AU - Younkin, SG

AU - The Alzheimer's Disease Neuroimaging, Initiative

AU - Jones, L

AU - Holmans, PA

AU - O'Donovan, M

AU - Owen, MJ

AU - Williams, J

PY - 2012/5

Y1 - 2012/5

N2 - We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

AB - We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

U2 - 10.1038/ng.803

DO - 10.1038/ng.803

M3 - Article (Academic Journal)

C2 - 21460840

VL - 43 (5)

SP - 429

EP - 435

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

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