Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

J C Lambert, C A Ibrahim-Verbaas, D Harold, A C Naj, R Sims, C Bellenguez, A L DeStafano, J C Bis, G W Beecham, B Grenier-Boley, G Russo, T A Thorton-Wells, N Jones, A V Smith, V Chouraki, C Thomas, M A Ikram, D Zelenika, B N Vardarajan, Y Kamatani, C F Lin, A Gerrish, H Schmidt, B Kunkle, M L Dunstan, A Ruiz, M T Bihoreau, S H Choi, C Reitz, F Pasquier, C Cruchaga, D Craig, N Amin, C Berr, O L Lopez, P L De Jager, V Deramecourt, J A Johnston, D Evans, S Lovestone, L Letenneur, F J Morón, D C Rubinsztein, G Eiriksdottir, K Sleegers, A M Goate, N Fiévet, M W Huentelman, M Gill, K Brown, M I Kamboh, L Keller, P Barberger-Gateau, B McGuiness, E B Larson, R Green, A J Myers, C Dufouil, S Todd, D Wallon, S Love, E Rogaeva, J Gallacher, P St George-Hyslop, J Clarimon, A Lleo, A Bayer, D W Tsuang, L Yu, M Tsolaki, P Bossù, G Spalletta, P Proitsi, J Collinge, S Sorbi, F Sanchez-Garcia, N C Fox, J Hardy, M C Deniz Naranjo, P Bosco, R Clarke, C Brayne, D Galimberti, M Mancuso, F Matthews; European Alzheimer's Disease Initiative (EADI); Genetic and Environmental Risk in Alzheimer's Disease; Alzheimer's Disease Genetic Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology; S Moebus, P Mecocci, M Del Zompo, W Maier, H Hampel, A Pilotto, M Bullido, F Panza, P Caffarra, B Nacmias, J R Gilbert, M Mayhaus, L Lannefelt, H Hakonarson, S Pichler, M M Carrasquillo, M Ingelsson, D Beekly, V Alvarez, F Zou, O Valladares, S G Younkin, E Coto, K L Hamilton-Nelson, W Gu, C Razquin, P Pastor, I Mateo, M J Owen, K M Faber, P V Jonsson, O Combarros, M C O'Donovan, L B Cantwell, H Soininen, D Blacker, S Mead, T H Mosley Jr, D A Bennett, T B Harris, L Fratiglioni, C Holmes, R F de Bruijn, P Passmore, T J Montine, K Bettens, J I Rotter, A Brice, K Morgan, T M Foroud, W A Kukull, D Hannequin, J F Powell, M A Nalls, K Ritchie, K L Lunetta, J S Kauwe, E Boerwinkle, M Riemenschneider, M Boada, M Hiltuenen, E R Martin, R Schmidt, D Rujescu, L S Wang, J F Dartigues, R Mayeux, C Tzourio, A Hofman, M M Nöthen, C Graff, B M Psaty, L Jones, J L Haines, P A Holmans, M Lathrop, M A Pericak-Vance, L J Launer, L A Farrer, C M van Duijn, C Van Broeckhoven, V Moskvina, S Seshadri, J Williams, G D Schellenberg, P Amouyel

Collaborators

A Alpérovitch, A Boland, M Delépoine, B Dubois, E Duron, J Epelbaum, C Van Cauwenberghe, S Engelborghs, R Vandenberghe, P P De Deyn, R Ferri, C Romano, C Caltagirone, M D Orfei, A Ciaramella, E Scarpini, C Fenoglio, G Siciliano, U Bonuccelli, S Bagnoli, L Bracco, V Bessi, R Cecchetti, P Bastgiani, A Squassina, D Seripa, A Frank-García, I Sastre, R Blesa, D Alcolea, M Suárez-Clavet, P Sánchez-Juan, C Muñoz Fernandez, Y Aladro Benito, H Thonberg, C Forshell, L Lilus, A Kinhult-Ståhlbom, V Giedraitis, L Kilander, R M Brundin, L Concari, S Helisalmi, A M Koivisto, A Haapasalo, V Solfrizzi, V Frisardi, J Ott, R M Carney, D C Mash, M S Albert, R L Albin, L G Apostolova, S E Arnold, M M Barmada, L L Barnes, T G Beach, E H Bigio, T D Bird, B F Boeve, J D Bowen, A Boxer, J R Burk, N J Cairns, C Cao, C S Carlson, S L Carroll, L B Chibnik, H C Chui, D G Clark, J Corneveaux, D G Cribbs, C DeCarli, S T DeKosky, F Y Demirci, M Dick, D W Dickson, R Duara, N Ertekin-Taner, K B Fallon, M R Farlow, S Ferris, M P Frosch, G R Galasko, M Ganguli, M Gearing, D H Geschwind, B Ghetti, S Gilman, J D Glass, J H Growdon, R L Hamilton, L E Harrell, E Head, L S Honig, C M Hulette, B T Hyman, G P Jarvik, G A Jicha, L W Jin, A Karydas, J S Kauwe, J A Kaye, R Kim, E H Koo, N W Kowall, J H Kramer, P Kramer, F M LaFerla, J J Lah, J B Levernez, A I Levey, G Li, A P Lieberman, C G Lyketsos, W J Mack, D C Marson, F Martiniuk, E Masliah, W C McCormick, S M McCurry, A N McDavid, A C McKee, M Mesulam, B L Miller, C A Miller, J W Miller, J C Morris, J R Murrell, J M Olichney, V S Pankratz, J E Parasi, E Peskind, R C Peterson, A Pierce, W W Poon, H Potter, J F Quinn, A Raj, M Raskind, E M Raiman, B Reisberg, J M Ringman, E D Roberson, H J Rosen, R N Rosenberg, M Sano, A J Saykin, J A Schneider, L S Schneider, W W Seely, A G Smith, J A Sonnen, S Spina, R A Stern, R E Tanzi, J Q Trojanowski, J C Troncoso, V M Van Deerlin, L J Van Eldik, H V Vinters, J P Vonsattel, S Weintraub, K A Welsh-Bohmer, J Williamson, R L Woltjer, C E Yu, R Barber, R Au, P A Wolf, A Beiser, S Debette, Q Yang, G Weinstein, A D Johnson, J Wang, A G Uitterlinden, F Rivadeneira, P J Koudstgaal, W T Longstreth Jr, J T Becker, L H Kuller, T Lumley, K Rice, M Garcia, T Aspelund, J J Marksteiner, P Dal-Bianco, A M Töglhofer, P Freudenberger, G Ransmayr, T Benke, A M Toeglhofer, J Bressler, M M Breteler, M Fornage, I Hernández, M Rosende Roca, M Ana Mauleón, M Alegrat, R RamÍrez-Lorca, A González-Perez, J Chapman, A Stretton, A Morgan, P G Kehoe, C Medway, J Lord, J Turton, N M Hooper, E Vardy, J D Warren, J M Schott, J Uphill, N Ryan, M Rossor, Y Ben-Shlomo, D Makrina, O Gkatzima, M Lupton, M Koutroumani, D Avramidou, A Germanou, F Jessen, S Riedel-Heller, M Dichgans, R Heun, H Kölsch, B Schürmann, C Herold, A Lacour, D Drichel, P Hoffman, J Kornhuber, W Gu, T Feulner, H van den Bussche, B Lawlor, A Lynch, D Mann, A D Smith, D Warden, G Wilcock, I Heuser, J Wiltgang, L Frölich, M Hüll, K Mayo, G Livingston, N J Bass, H Gurling, A McQuillen, R Gwilliam, P Deloukas, A Al-Chalabi, C E Shaw, A B Singleton, R Guerreiro, K H Jöckel, N Klopp, H E Wichmann, D W Dickson, N R Graff-Radford, L Ma, G Bisceglio, E Fisher, N Warner, S Pickering-Brown

PMID: 24162737
PMCID: PMC3896259
DOI: 10.1038/ng.2802

Meta-Analysis

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

J C Lambert et al. Nat Genet. 2013 Dec.

. 2013 Dec;45(12):1452-8.

doi: 10.1038/ng.2802. Epub 2013 Oct 27.

Authors

Collaborators

A Alpérovitch, A Boland, M Delépoine, B Dubois, E Duron, J Epelbaum, C Van Cauwenberghe, S Engelborghs, R Vandenberghe, P P De Deyn, R Ferri, C Romano, C Caltagirone, M D Orfei, A Ciaramella, E Scarpini, C Fenoglio, G Siciliano, U Bonuccelli, S Bagnoli, L Bracco, V Bessi, R Cecchetti, P Bastgiani, A Squassina, D Seripa, A Frank-García, I Sastre, R Blesa, D Alcolea, M Suárez-Clavet, P Sánchez-Juan, C Muñoz Fernandez, Y Aladro Benito, H Thonberg, C Forshell, L Lilus, A Kinhult-Ståhlbom, V Giedraitis, L Kilander, R M Brundin, L Concari, S Helisalmi, A M Koivisto, A Haapasalo, V Solfrizzi, V Frisardi, J Ott, R M Carney, D C Mash, M S Albert, R L Albin, L G Apostolova, S E Arnold, M M Barmada, L L Barnes, T G Beach, E H Bigio, T D Bird, B F Boeve, J D Bowen, A Boxer, J R Burk, N J Cairns, C Cao, C S Carlson, S L Carroll, L B Chibnik, H C Chui, D G Clark, J Corneveaux, D G Cribbs, C DeCarli, S T DeKosky, F Y Demirci, M Dick, D W Dickson, R Duara, N Ertekin-Taner, K B Fallon, M R Farlow, S Ferris, M P Frosch, G R Galasko, M Ganguli, M Gearing, D H Geschwind, B Ghetti, S Gilman, J D Glass, J H Growdon, R L Hamilton, L E Harrell, E Head, L S Honig, C M Hulette, B T Hyman, G P Jarvik, G A Jicha, L W Jin, A Karydas, J S Kauwe, J A Kaye, R Kim, E H Koo, N W Kowall, J H Kramer, P Kramer, F M LaFerla, J J Lah, J B Levernez, A I Levey, G Li, A P Lieberman, C G Lyketsos, W J Mack, D C Marson, F Martiniuk, E Masliah, W C McCormick, S M McCurry, A N McDavid, A C McKee, M Mesulam, B L Miller, C A Miller, J W Miller, J C Morris, J R Murrell, J M Olichney, V S Pankratz, J E Parasi, E Peskind, R C Peterson, A Pierce, W W Poon, H Potter, J F Quinn, A Raj, M Raskind, E M Raiman, B Reisberg, J M Ringman, E D Roberson, H J Rosen, R N Rosenberg, M Sano, A J Saykin, J A Schneider, L S Schneider, W W Seely, A G Smith, J A Sonnen, S Spina, R A Stern, R E Tanzi, J Q Trojanowski, J C Troncoso, V M Van Deerlin, L J Van Eldik, H V Vinters, J P Vonsattel, S Weintraub, K A Welsh-Bohmer, J Williamson, R L Woltjer, C E Yu, R Barber, R Au, P A Wolf, A Beiser, S Debette, Q Yang, G Weinstein, A D Johnson, J Wang, A G Uitterlinden, F Rivadeneira, P J Koudstgaal, W T Longstreth Jr, J T Becker, L H Kuller, T Lumley, K Rice, M Garcia, T Aspelund, J J Marksteiner, P Dal-Bianco, A M Töglhofer, P Freudenberger, G Ransmayr, T Benke, A M Toeglhofer, J Bressler, M M Breteler, M Fornage, I Hernández, M Rosende Roca, M Ana Mauleón, M Alegrat, R RamÍrez-Lorca, A González-Perez, J Chapman, A Stretton, A Morgan, P G Kehoe, C Medway, J Lord, J Turton, N M Hooper, E Vardy, J D Warren, J M Schott, J Uphill, N Ryan, M Rossor, Y Ben-Shlomo, D Makrina, O Gkatzima, M Lupton, M Koutroumani, D Avramidou, A Germanou, F Jessen, S Riedel-Heller, M Dichgans, R Heun, H Kölsch, B Schürmann, C Herold, A Lacour, D Drichel, P Hoffman, J Kornhuber, W Gu, T Feulner, H van den Bussche, B Lawlor, A Lynch, D Mann, A D Smith, D Warden, G Wilcock, I Heuser, J Wiltgang, L Frölich, M Hüll, K Mayo, G Livingston, N J Bass, H Gurling, A McQuillen, R Gwilliam, P Deloukas, A Al-Chalabi, C E Shaw, A B Singleton, R Guerreiro, K H Jöckel, N Klopp, H E Wichmann, D W Dickson, N R Graff-Radford, L Ma, G Bisceglio, E Fisher, N Warner, S Pickering-Brown

PMID: 24162737
PMCID: PMC3896259
DOI: 10.1038/ng.2802

Abstract

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

PubMed Disclaimer

Figures

**Figure 1**
Manhattan plot of stage 1 for genome-wide association with Alzheimer’s disease (17,008 cases and 37,154 controls). The threshold for genome-wide significance (P < 5 × 10⁻⁸) is indicated by the red line. Genes previously identified by GWAS are shown in black, and newly associated genes are shown in red. Red diamonds represent SNPs with the smallest P values in the overall analysis.

**Figure 2**
Regional plot for the *PTK2B-CLU* locus (17,008 cases and 37,154 controls).

See this image and copyright information in PMC

References

1. Corder EH, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. - PubMed
1. Genin E, et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry. 2011;16:903–907. - PMC - PubMed
1. Lambert J-C, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 2009;41:1094–1099. - PubMed
1. Harold D, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 2009;41:1088–1093. - PMC - PubMed
1. Seshadri S, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. J. Am. Med. Assoc. 2010;303:1832–1840. - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Collaborators

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Authors

Collaborators

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous