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

P Hollingworth; D Harold; R Sims; A Gerrish; JC Lambert; MM Carrasquillo; R Abraham; ML Hamshere; JS Pahwa; V Moskvina; K Dowzell; N Jones; A Stretton; C Thomas; 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; KS Brown; PA Passmore; D Craig; B McGuinness; S Todd; C Holmes; D Mann; AD Smith; H Beaumont; D Warden; G Wilcock; S Love; PG Kehoe; NM Hooper; ERLC Vardy; J Hardy; S Mead; NC Fox; M Rossor; J Collinge; W Maier; F Jessen; E Ruther; B Schurmann; R Heun; H Kolsch; H van den Bussche; I Heuser; J Kornhuber; J Wiltfang; M Dichgans; L Frolich; H Hampel; J Gallacher; M Hull; D Rujescu; I Giegling; AM Goate; JSK Kauwe; C Cruchaga; P Nowotny; JC Morris; K Mayo; K (Kristel) Sleegers; K Bettens; S Engelborghs; PP de Deyn; C van Broeckhoven; G Livingston; NJ Bass; H Gurling; A McQuillin; R Gwilliam; P Deloukas; A Al-Chalabi; CE Shaw; M Tsolaki; AB Singleton; R Guerreiro; TW Muhleisen; MM Nothen; S Moebus; KH Jockel; N Klopp; HE Wichmann; VS Pankratz; SB Sando; JO Aasly; M Barcikowska; ZK Wszolek; DW Dickson; NR Graff-Radford; RC Petersen; Cornelia Duijn; Monique Breteler; Arfan Ikram; AL DeStefano; AL Fitzpatrick; O Lopez; LJ (Lenore) Launer; S Seshadri; C Berr; D Campion; J Epelbaum; JF Dartigues; C Tzourio; A Alperovitch; M Lathrop; TM Feulner; P Friedrich; C Riehle; M Krawczak; S Schreiber; M Mayhaus; S Nicolhaus; S Wagenpfeil; S Steinberg; H Stefansson; K Stefansson; J Snaedal; S Bjornsson; PV Jonsson; V Chouraki; B Genier-Boley; M Hiltunen; H Soininen; O Combarros; D Zelenika; M Delepine; MJ Bullido; F Pasquier; I Mateo; A Frank-Garcia; E Porcellini; O Hanon; E Coto; V Alvarez; P Bosco; G Siciliano; M Mancuso; F Panza; V Solfrizzi; B Nacmias; S Sorbi; P Bossu; P Piccardi; B Arosio; G Annoni; D Seripa; A Pilotto; E Scarpini; D Galimberti; A Brice; D Hannequin; F Licastro; L Jones; PA Holmans; T Jonsson; M Riemenschneider; K Morgan; SG Younkin; MJ Owen; M O'Donovan; P Amouyel; 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, D Harold, R Sims, A Gerrish, JC Lambert, MM Carrasquillo, R Abraham, ML Hamshere, JS Pahwa, V Moskvina, K Dowzell, N Jones, A Stretton, C Thomas, A Richards, D Ivanov, C Widdowson, J Chapman, S Lovestone, J PowellP Proitsi, MK Lupton, C Brayne, DC Rubinsztein, M Gill, B Lawlor, A Lynch, KS Brown, PA Passmore, D Craig, B McGuinness, S Todd, C Holmes, D Mann, AD Smith, H Beaumont, D Warden, G Wilcock, S Love, PG Kehoe, NM Hooper, ERLC Vardy, J Hardy, S Mead, NC Fox, M Rossor, J Collinge, W Maier, F Jessen, E Ruther, B Schurmann, R Heun, H Kolsch, H van den Bussche, I Heuser, J Kornhuber, J Wiltfang, M Dichgans, L Frolich, H Hampel, J Gallacher, M Hull, D Rujescu, I Giegling, AM Goate, JSK Kauwe, C Cruchaga, P Nowotny, JC Morris, K Mayo, K (Kristel) Sleegers, K Bettens, S Engelborghs, PP de Deyn, C van Broeckhoven, G Livingston, NJ Bass, H Gurling, A McQuillin, R Gwilliam, P Deloukas, A Al-Chalabi, CE Shaw, M Tsolaki, AB Singleton, R Guerreiro, TW Muhleisen, MM Nothen, S Moebus, KH Jockel, N Klopp, HE Wichmann, VS Pankratz, SB Sando, JO Aasly, M Barcikowska, ZK Wszolek, DW Dickson, NR Graff-Radford, RC Petersen, Cornelia Duijn, Monique Breteler, Arfan Ikram, AL DeStefano, AL Fitzpatrick, O Lopez, LJ (Lenore) Launer, S Seshadri, C Berr, D Campion, J Epelbaum, JF Dartigues, C Tzourio, A Alperovitch, M Lathrop, TM Feulner, P Friedrich, C Riehle, M Krawczak, S Schreiber, M Mayhaus, S Nicolhaus, S Wagenpfeil, S Steinberg, H Stefansson, K Stefansson, J Snaedal, S Bjornsson, PV Jonsson, V Chouraki, B Genier-Boley, M Hiltunen, H Soininen, O Combarros, D Zelenika, M Delepine, MJ Bullido, F Pasquier, I Mateo, A Frank-Garcia, E Porcellini, O Hanon, E Coto, V Alvarez, P Bosco, G Siciliano, M Mancuso, F Panza, V Solfrizzi, B Nacmias, S Sorbi, P Bossu, P Piccardi, B Arosio, G Annoni, D Seripa, A Pilotto, E Scarpini, D Galimberti, A Brice, D Hannequin, F Licastro, L Jones, PA Holmans, T Jonsson, M Riemenschneider, K Morgan, SG Younkin, MJ Owen, M O'Donovan, P Amouyel, J Williams

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

1590 Citations (Scopus)

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 x 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 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 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 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 10(-10)).

Original language	Undefined/Unknown
Pages (from-to)	429-435
Number of pages	7
Journal	Nature Genetics
Volume	43
Issue number	5
DOIs	https://doi.org/10.1038/ng.803
Publication status	Published - 2011

Research programs

EMC COEUR-09
EMC NIHES-01-64-01
EMC NIHES-01-64-02
EMC NIHES-03-30-01

Access to Document

10.1038/ng.803

http://hdl.handle.net/1765/34220

Cite this

Hollingworth, P., Harold, D., Sims, R., Gerrish, A., Lambert, JC., Carrasquillo, MM., Abraham, R., Hamshere, ML., Pahwa, JS., Moskvina, V., Dowzell, K., Jones, N., Stretton, A., Thomas, C., Richards, A., Ivanov, D., Widdowson, C., Chapman, J., Lovestone, S., ... Williams, J. (2011). Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genetics, 43(5), 429-435. https://doi.org/10.1038/ng.803

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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 x 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 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 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 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 10(-10)).",

author = "P Hollingworth and D Harold and R Sims and A Gerrish and JC Lambert and MM Carrasquillo and R Abraham and ML Hamshere and JS Pahwa and V Moskvina and K Dowzell and N Jones and A Stretton and C Thomas 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 KS Brown and PA Passmore and D Craig and B McGuinness and S Todd and C Holmes and D Mann and AD Smith and H Beaumont and D Warden and G Wilcock and S Love and PG Kehoe and NM Hooper and ERLC Vardy and J Hardy and S Mead and NC Fox and M Rossor and J Collinge and W Maier and F Jessen and E Ruther and B Schurmann and R Heun and H Kolsch and {van den Bussche}, H and I Heuser and J Kornhuber and J Wiltfang and M Dichgans and L Frolich and H Hampel and J Gallacher and M Hull 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 Sleegers, {K (Kristel)} 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 R Gwilliam and P Deloukas and A Al-Chalabi and CE Shaw and M Tsolaki and AB Singleton and R Guerreiro and TW Muhleisen and MM Nothen and S Moebus and KH Jockel and N Klopp and HE Wichmann and VS Pankratz and SB Sando and JO Aasly and M Barcikowska and ZK Wszolek and DW Dickson and NR Graff-Radford and RC Petersen and Cornelia Duijn and Monique Breteler and Arfan Ikram and AL DeStefano and AL Fitzpatrick and O Lopez and Launer, {LJ (Lenore)} and S Seshadri and C Berr and D Campion and J Epelbaum and JF Dartigues and C Tzourio and A Alperovitch and M Lathrop and TM Feulner and P Friedrich and C Riehle and M Krawczak and S Schreiber and M Mayhaus and S Nicolhaus and S Wagenpfeil and S Steinberg and H Stefansson and K Stefansson and J Snaedal and S Bjornsson and PV Jonsson and V Chouraki and B Genier-Boley and M Hiltunen and H Soininen and O Combarros and D Zelenika and M Delepine and MJ Bullido and F Pasquier and I Mateo and A Frank-Garcia and E Porcellini and O Hanon and E Coto and V Alvarez and P Bosco and G Siciliano and M Mancuso and F Panza and V Solfrizzi and B Nacmias and S Sorbi and P Bossu and P Piccardi and B Arosio and G Annoni and D Seripa and A Pilotto and E Scarpini and D Galimberti and A Brice and D Hannequin and F Licastro and L Jones and PA Holmans and T Jonsson and M Riemenschneider and K Morgan and SG Younkin and MJ Owen and M O'Donovan and P Amouyel and J Williams",

year = "2011",

doi = "10.1038/ng.803",

language = "Undefined/Unknown",

volume = "43",

pages = "429--435",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

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Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, JC, Carrasquillo, MM, Abraham, R, Hamshere, ML, Pahwa, JS, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, 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, Brown, KS, Passmore, PA, Craig, D, McGuinness, B, Todd, S, Holmes, C, Mann, D, Smith, AD, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, PG, Hooper, NM, Vardy, ERLC, Hardy, J, Mead, S, Fox, NC, Rossor, M, Collinge, J, Maier, W, Jessen, F, Ruther, E, Schurmann, B, Heun, R, Kolsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frolich, L, Hampel, H, Gallacher, J, Hull, M, 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, 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, Pankratz, VS, Sando, SB, Aasly, JO, Barcikowska, M, Wszolek, ZK, Dickson, DW, Graff-Radford, NR, Petersen, RC, Duijn, C, Breteler, M, Ikram, A, DeStefano, AL, Fitzpatrick, AL, Lopez, O, Launer, LJ, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, JF, Tzourio, C, Alperovitch, A, Lathrop, M, Feulner, TM, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snaedal, J, Bjornsson, S, Jonsson, PV, Chouraki, V, Genier-Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, MJ, Pasquier, F, Mateo, I, Frank-Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossu, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, PA, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, SG, Owen, MJ, O'Donovan, M, Amouyel, P & Williams, J 2011, 'Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease', Nature Genetics, vol. 43, 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 - Harold, D

AU - Sims, R

AU - Gerrish, A

AU - Lambert, JC

AU - Carrasquillo, MM

AU - Abraham, R

AU - Hamshere, ML

AU - Pahwa, JS

AU - Moskvina, V

AU - Dowzell, K

AU - Jones, N

AU - Stretton, A

AU - Thomas, C

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 - Brown, KS

AU - Passmore, PA

AU - Craig, D

AU - McGuinness, B

AU - Todd, S

AU - Holmes, C

AU - Mann, D

AU - Smith, AD

AU - Beaumont, H

AU - Warden, D

AU - Wilcock, G

AU - Love, S

AU - Kehoe, PG

AU - Hooper, NM

AU - Vardy, ERLC

AU - Hardy, J

AU - Mead, S

AU - Fox, NC

AU - Rossor, M

AU - Collinge, J

AU - Maier, W

AU - Jessen, F

AU - Ruther, E

AU - Schurmann, B

AU - Heun, R

AU - Kolsch, H

AU - van den Bussche, H

AU - Heuser, I

AU - Kornhuber, J

AU - Wiltfang, J

AU - Dichgans, M

AU - Frolich, L

AU - Hampel, H

AU - Gallacher, J

AU - Hull, M

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 (Kristel)

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, R

AU - Deloukas, P

AU - Al-Chalabi, A

AU - Shaw, CE

AU - Tsolaki, M

AU - Singleton, AB

AU - Guerreiro, R

AU - Muhleisen, TW

AU - Nothen, MM

AU - Moebus, S

AU - Jockel, KH

AU - Klopp, N

AU - Wichmann, HE

AU - Pankratz, VS

AU - Sando, SB

AU - Aasly, JO

AU - Barcikowska, M

AU - Wszolek, ZK

AU - Dickson, DW

AU - Graff-Radford, NR

AU - Petersen, RC

AU - Duijn, Cornelia

AU - Breteler, Monique

AU - Ikram, Arfan

AU - DeStefano, AL

AU - Fitzpatrick, AL

AU - Lopez, O

AU - Launer, LJ (Lenore)

AU - Seshadri, S

AU - Berr, C

AU - Campion, D

AU - Epelbaum, J

AU - Dartigues, JF

AU - Tzourio, C

AU - Alperovitch, A

AU - Lathrop, M

AU - Feulner, TM

AU - Friedrich, P

AU - Riehle, C

AU - Krawczak, M

AU - Schreiber, S

AU - Mayhaus, M

AU - Nicolhaus, S

AU - Wagenpfeil, S

AU - Steinberg, S

AU - Stefansson, H

AU - Stefansson, K

AU - Snaedal, J

AU - Bjornsson, S

AU - Jonsson, PV

AU - Chouraki, V

AU - Genier-Boley, B

AU - Hiltunen, M

AU - Soininen, H

AU - Combarros, O

AU - Zelenika, D

AU - Delepine, M

AU - Bullido, MJ

AU - Pasquier, F

AU - Mateo, I

AU - Frank-Garcia, A

AU - Porcellini, E

AU - Hanon, O

AU - Coto, E

AU - Alvarez, V

AU - Bosco, P

AU - Siciliano, G

AU - Mancuso, M

AU - Panza, F

AU - Solfrizzi, V

AU - Nacmias, B

AU - Sorbi, S

AU - Bossu, P

AU - Piccardi, P

AU - Arosio, B

AU - Annoni, G

AU - Seripa, D

AU - Pilotto, A

AU - Scarpini, E

AU - Galimberti, D

AU - Brice, A

AU - Hannequin, D

AU - Licastro, F

AU - Jones, L

AU - Holmans, PA

AU - Jonsson, T

AU - Riemenschneider, M

AU - Morgan, K

AU - Younkin, SG

AU - Owen, MJ

AU - O'Donovan, M

AU - Amouyel, P

AU - Williams, J

PY - 2011

Y1 - 2011

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 x 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 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 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 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 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 x 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 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 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 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 10(-10)).

U2 - 10.1038/ng.803

DO - 10.1038/ng.803

M3 - Article

C2 - 21460840

SN - 1061-4036

VL - 43

SP - 429

EP - 435

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -