Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Manhattan plot of stage 1 for genome-wide association with Alzheimer's disease (17,008 cases and 37,154 controls).
Figure 2

Similar content being viewed by others

References

  1. Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Genin, E. et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16, 903–907 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lambert, J.-C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41, 1094–1099 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41, 1088–1093 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. J. Am. Med. Assoc. 303, 1832–1840 (2010).

    Article  CAS  Google Scholar 

  6. Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43, 429–435 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Naj, A.C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43, 436–441 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Miyashita, A. et al. SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians. PLoS ONE 8, e58618 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78, 256–268 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nalls, M.A. et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377, 641–649 (2011).

    Article  PubMed  Google Scholar 

  14. Rogaeva, E. et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat. Genet. 39, 168–177 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pottier, C. et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol. Psychiatry 17, 875–879 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Pandey, P. et al. Activation of p38 mitogen-activated protein kinase by PYK2/related adhesion focal tyrosine kinase–dependent mechanism. J. Biol. Chem. 274, 10140–10144 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Huang, Y. et al. CAKβ/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. Neuron 29, 485–496 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Williamson, R. et al. CRMP2 hyperphosphorylation is characteristic of Alzheimer's disease and not a feature common to other neurodegenerative diseases. J. Alzheimers Dis. 27, 615–625 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Sulem, P. et al. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat. Genet. 39, 1443–1452 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Adeyemo, A. et al. A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet. 5, e1000564 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Larsson, M. et al. GWAS findings for human iris patterns: associations with variants in genes that influence normal neuronal pattern development. Am. J. Hum. Genet. 89, 334–343 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kajiho, H. et al. RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. J. Cell Sci. 116, 4159–4168 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Chapuis, J. et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol. Psychiatry doi:10.1038/mp.2013.1 (12 February 2013).

  24. He, F. et al. Structural insight into the zinc finger CW domain as a histone modification reader. Structure 18, 1127–1139 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Yokoyama, K. et al. NYAP: a phosphoprotein family that links PI3K to WAVE1 signalling in neurons. EMBO J. 30, 4739–4754 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gallo, J.M. & Spickett, C. The role of CELF proteins in neurological disorders. RNA Biol. 7, 474–479 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Del Villar, K. & Miller, C.A. Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons. Proc. Natl. Acad. Sci. USA 101, 4210–4215 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Duriez, B. et al. A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia. Proc. Natl. Acad. Sci. USA 104, 3336–3341 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pluskota, E. et al. The integrin coactivator kindlin-2 plays a critical role in angiogenesis in mice and zebrafish. Blood 117, 4978–4987 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shulman, J.M. et al. Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. Hum. Mol. Genet. doi:10.1093/hmg/ddt478 (9 October 2013).

  31. Kirsch, K.H., Georgescu, M.M., Ishimaru, S. & Hanafusa, H. CMS: an adapter molecule involved in cytoskeletal rearrangements. Proc. Natl. Acad. Sci. USA 96, 6211–6216 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bao, M. et al. CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. J. Immunol. 189, 786–792 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Brauer, H. et al. Leukemia-associated mutations in SHIP1 inhibit its enzymatic activity, interaction with the GM-CSF receptor and Grb2, and its ability to inactivate PI3K/AKT signaling. Cell. Signal. 24, 2095–2101 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Le Meur, N. et al. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J. Med. Genet. 47, 22–29 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Akhtar, M.W. et al. In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival. PLoS ONE 7, e34863 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid β. Neuron 78, 631–643 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lambert, J.C. & Amouyel, P. Genetics of Alzheimer's disease: new evidences for an old hypothesis? Curr. Opin. Genet. Dev. 21, 295–301 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Lambert, J.-C. et al. Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis. J. Alzheimers Dis. 20, 1107–1118 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Jones, L. et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 5, e13950 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Brouwers, N. et al. Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol. Psychiatry 17, 223–233 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Bettens, K., Sleegers, K. & Van Broeckhoven, C. Genetic insights in Alzheimer's disease. Lancet Neurol. 12, 92–104 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies via imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    PubMed  PubMed Central  Google Scholar 

  48. Bellenguez, C. et al. A robust clustering algorithm for identifying problematic samples in genome-wide association studies. Bioinformatics 28, 134–135 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mägi, R. & Morris, A.P. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Levin, M.L. The occurrence of lung cancer in man. Acta Unio Int. Contra Cancrum 9, 531–541 (1953).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was made possible by the generous participation of the control subjects, the patients and their families. iSelect chips were funded by the French National Foundation on Alzheimer's Disease and Related Disorders. Data management involved the Centre National de Génotypage and was supported by the Institut Pasteur de Lille, INSERM, FRC (Fondation pour la Recherche sur le Cerveau) and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease). The French National Foundation on Alzheimer's Disease and Related Disorders and the Alzheimer's Association (Chicago, Illinois) grant supported in-person meetings and communication for IGAP, and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses.

GERAD was supported by the Wellcome Trust, the MRC, Alzheimer's Research UK (ARUK) and the Welsh government. ADGC and CHARGE were supported by the US National Institutes of Health, National Institute on Aging (NIH-NIA), including grants U01 AG032984 and R01 AG033193 (additional US National Institutes of Health grant numbers are listed in the Supplementary Note). CHARGE was also supported by Erasmus Medical Center and Erasmus University.

Complete acknowledgments are detailed in the Supplementary Note.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

Study concept and design: J.-C.L., C.A.I.-V., D. Harold, A.C.N., A.L.D., J.C.B., A.V.S., M.A.I., H. Schmidt, A.L.F., V.G., O.L.L., D.W.T., D. Blacker, T.H.M., T.B.H., J.I.R., W.A.K., M. Boada, R. Schmidt, R.M., A.H., B.M.P., J.L.H., P.A.H., M.L., M.A.P.-V., L.J.L., L.A.F., C.M.v.D., V.M., S. Seshadri, J.W., G.D.S. and P.A. Acquisition of data: J.-C.L., C.A.I.-V., D. Harold, C. Bellenguez, R. Sims, G.J., B.G.-B., G.R., N.J., V.C., C. Thomas, D.Z., Y.K., A.G., H. Schmidt, M.L.D., M.-T.B., S.-H.C., P.H., V.G., C. Baldwin, C.C., C. Berr, O.L.L., P.L.D.J., D.E., L. Letenneur, G.E., K.S., A.M.G., N.F., M.J.H., M.I.K., E.B.L., A.J.M., C.D., S.T., S. Love, E.R., P.S.G.-H., L.Y., M.M.C., D. Beekly, F.Z., O.V., S.G.Y., W.G., M.J.O., K.M.F., P.V.J., M.C.O., L.B.C., D.A.B., T.B.H., R.F.A.G.d.B., T.J.M., J.I.R., K.M., T.M.F., W.A.K., J.F.P., M.A.N., K.R., J.S.K.K., E.B., M.R., M. Boada, L.-S.W., J.-F.D., C. Tzourio, M.M.N., B.M.P., L.J., J.L.H., M.L., L.J.L., L.A.F., A.H., C.M.v.D., S. Seshadri, J.W., G.D.S. and P.A. Sample contribution: A. Ruiz, F. Pasquier, A. Ramirez, O.H., J.D.B., D. Campion, P.K.C., C. Baldwin, T.B., C.C., D. Craig, V.D., J.A.J., S. Lovestone, F.J.M., D.C.R., K.S., A.M.G., N.F., M.G., K. Brown, M.I.K., L.K., P.B.-G., B.M., R.G., A.J.M., D.W., E.R., J.G., P.S.G.-H., J.C., A.L., A. Bayer, M.T., P. Bossù, G.S., P. Proitsi, J.C., S. Sorbi, F.S.-G., N.C.F., J.H., M.C.D.N., P. Bosco, R.C., C. Brayne, D.G., M. Mancuso, F.M., S. Moebus, P.M., M.D.Z., W.M., H. Hampel, A.P., M. Bullido, F. Panza, P.C., B.N., M. Mayhaus, L. Lannfelt, H. Hakonarson, S.P., M.M.C., M.I., V.A., S.G.Y., E.C., C. Razquin, P. Pastor, I.M., O.C., H. Soininen, S. Mead, D.A.B., L.F., C.H., P. Passmore, T.J.M., K. Bettens, A. Brice, D. Hannequin, K.R., M.R., M.H., D.R., C.G. and C.V.B. Data analysis: C.A.I.-V., D. Harold, A.C.N., R. Sims, C. Bellenguez, G.J., A.L.D., J.C.B., G.W.B., B.G.-B., G.R., T.A.T.-W., N.J., A.V.S., V.C., M.A.I., D.Z., Y.K., B.N.V., C.-F.L., A.G., B.K., C. Reitz, J.R.G., O.V., W.A.K., K.L.L., K.L.H.-N., E.R.M., L.-S.W., B.M.P., M.L., V.M. and J.W. Statistical analysis and interpretation: J.-C.L., C.A.I.-V., D. Harold, A.C.N., C. Bellenguez, G.J., A.L.D., J.C.B., G.W.B., T.A.T.-W., A.V.S., V.C., M.A.I., B.N.V., Y.K., C.-F.L., B.K., C. Reitz, A.L.F., N.A., J.R.G., R.F.A.G.d.B., W.A.K., K.L.L., E.R.M., L.-S.W., B.M.P., L.J., J.L.H., P.A.H., M.A.P.-V., L.J.L., L.A.F., C.M.v.D., V.M., S. Seshadri, J.W., G.D.S. and P.A. Drafting of the manuscript: J.-C.L., C.A.I.-V., D. Harold, A.C.N., C. Bellenguez, A.L.D., J.C.B., A.V.S., R.M., B.M.P., J.L.H., M.A.P.-V., L.J.L., L.A.F., C.M.v.D., C.V.B., S. Seshadri, J.W., G.D.S. and P.A.

Corresponding authors

Correspondence to Julie Williams or Philippe Amouyel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Full lists of members and affiliations appear in the Supplementary Note

Full lists of members and affiliations appear in the Supplementary Note

Full lists of members and affiliations appear in the Supplementary Note

Full lists of members and affiliations appear in the Supplementary Note

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–18, Supplementary Tables 1–10 and Supplementary Note (PDF 3193 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lambert, JC., Ibrahim-Verbaas, C., Harold, D. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45, 1452–1458 (2013). https://doi.org/10.1038/ng.2802

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2802

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing