Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease


The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (PM) = 1.7 × 10−9, joint analysis P (PJ) = 1.7 × 10−9; stages 1, 2 and 3, PM = 8.2 × 10−12), CD2AP (rs9349407; stages 1, 2 and 3, PM = 8.6 × 10−9), EPHA1 (rs11767557; stages 1, 2 and 3, PM = 6.0 × 10−10) and CD33 (rs3865444; stages 1, 2 and 3, PM = 1.6 × 10−9). We also replicated previous associations at CR1 (rs6701713; PM = 4.6 × 10−10, PJ = 5.2 × 10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9 × 10−8), BIN1 (rs7561528; PM = 4.0 × 10−14, PJ = 5.2 × 10−14) and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0 × 10−10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility1,2,3.

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Figure 1: Regional association plots from the three-stage meta-analysis with LOAD.


  1. 1

    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).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 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).

    CAS  Article  Google Scholar 

  4. 4

    Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A. & Evans, D.A. Alzheimer disease in the US population—prevalence estimates using the 2000 census. Arch. Neurol. 60, 1119–1122 (2003).

    Article  Google Scholar 

  5. 5

    Alzheimer's Association. Alzheimer's disease facts and figures. Alzheimer's Dement. 5, 234–270 (2009).

  6. 6

    Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    CAS  Article  Google Scholar 

  7. 7

    Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Rogaev, E.I. et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376, 775–778 (1995).

    CAS  Article  Google Scholar 

  9. 9

    Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973–977 (1995).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    Gatz, M. et al. Heritability for Alzheimer's disease: the study of dementia in Swedish twins. J. Gerontol. A Biol. Sci. Med. Sci. 52, M117–M125 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. advance online publication, doi:10.1038/ng.803 (3 April 2011).

  13. 13

    Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Ioannidis, J.P., Rosenberg, P.S., Goedert, J.J. & O'Brien, T.R. Commentary: meta-analysis of individual participants' data in genetic epidemiology. Am. J. Epidemiol. 156, 204–210 (2002).

    Article  Google Scholar 

  15. 15

    Bertram, L. et al. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 83, 623–632 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Reiman, E.M. et al. GAB2 alleles modify Alzheimer's risk in APOE ɛ4 carriers. Neuron 54, 713–720 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Carrasquillo, M.M. et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat. Genet. 41, 192–198 (2009).

    CAS  Article  Google Scholar 

  18. 18

    Li, H. et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch. Neurol. 65, 45–53 (2008).

    Article  Google Scholar 

  19. 19

    Naj, A.C. et al. Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet. 6, e1001130 (2010).

    Article  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Jun, G. et al. Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch. Neurol. 67, 1473–1484 (2010).

    Article  Google Scholar 

  22. 22

    Rockhill, B., Newman, B. & Weinberg, C. Use and misuse of population attributable fractions. Am. J. Public Health 88, 15–19 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Ku, C.S., Loy, E.Y., Pawitan, Y. & Chia, K.S. The pursuit of genome-wide association studies: where are we now? J. Hum. Genet. 55, 195–206 (2010).

    CAS  Article  Google Scholar 

  24. 24

    Florez, J.C. Clinical review: the genetics of type 2 diabetes: a realistic appraisal in 2008. J. Clin. Endocrinol. Metab. 93, 4633–4642 (2008).

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

    McPeek, M.S. & Sun, L. Statistical tests for detection of misspecified relationships by use of genome-screen data. Am. J. Hum. Genet. 66, 1076–1094 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. GRR: graphical representation of relationship errors. Bioinformatics 17, 742–743 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Li, Y. & Abecasis, G.R. Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

    Google Scholar 

  29. 29

    Wittwer, C.T. et al. The LightCycler: a microvolume multisample fluorimeter with rapid temperature control. Biotechniques 22, 176–181 (1997).

    CAS  Article  Google Scholar 

  30. 30

    Ahmadian, A. et al. Single-nucleotide polymorphism analysis by pyrosequencing. Anal. Biochem. 280, 103–110 (2000).

    CAS  Article  Google Scholar 

  31. 31

    Hixson, J.E. & Vernier, D.T. Restriction isotyping of human of human apolipoprotien E by gene amplification and cleavage with HhaI. J. Liped Res. 31, 545–548 (1990).

    CAS  Google Scholar 

  32. 32

    Lai, E., Riley, J., Purvis, I. & Roses, A. A 4-Mb high-density single nucleotide polymorphism-based map around human APOE. Genomics 54, 31–38 (1998).

    CAS  Article  Google Scholar 

  33. 33

    Pritchard, J.K., Stephens, M., Rosenberg, N.A. & Donnelly, P. Association mapping in structured populations. Am. J. Hum. Genet. 67, 170–181 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Pritchard, J.K., Stephens, M. & Donnelly, P.J. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Carey, V.J. Ported to R by Lumley, T. (versions 3.13,4.4) & Ripley, B. (version 4.13). GEE: Generalized Estimation Equation Solver. R package version 4.13-15. <> (2010).

  37. 37

    Chen, M.H. & Yang, Q. GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 26, 580–581 (2010).

    Article  Google Scholar 

  38. 38

    R Development Core Team. R. A language and environment for statistical computing. (R Foundation for Statistical Computing, Vienna, Austria, 2009).

  39. 39

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

    CAS  Article  Google Scholar 

  40. 40

    Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

    Article  Google Scholar 

  41. 41

    Higgins, J.P., Thompson, S.G., Deeks, J.J. & Altman, D.G. Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557–560 (2003).

    Article  Google Scholar 

  42. 42

    Abecasis, G.R. & Wigginton, J.E. Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am. J. Hum. Genet. 77, 754–767 (2005).

    CAS  Article  Google Scholar 

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The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Boston University, P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG009029, R01 AG017173, R01 AG025259; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377; Emory University, AG025688; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona/TGEN, P30 AG019610, R01 AG031581, R01 NS059873; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136, UO1 AG06781, UO1 HG004610; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank C. Phelps, M. Morrison-Bogorad and M. Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the Veterans Affairs Administration. P.S.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.

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Sample collection, phenotyping and data management: J.D. Buxbaum, G.P.J., P.K.C., E.B.L., T.D.B., B.F.B., N.R.G.-R., P.L.D., D.E., J.A. Schneider, M.M.C., N.E.-T., S.G.Y., C.C., J.S.K.K., P.N., P.K., J.H., M.J.H., A.J.M., M.M.B., F.Y.D., C.T.B., R.C.G., E.R., P.S.G.-H., S.E.A., R.B., T.B., E.H.B., J.D. Bowen, A.B., J.R.B., N.J.C., C.S.C., S.L.C., H.C.C., D.G.C., J.C., C.W.C., J.L.C., C.D., S.T.D., R.D.-A., M.D., D.W.D., W.G.E., K.M.F., K.B.F., M.R.F., S.F., M.P.F., D.R.G., M. Ganguli, M. Gearing, D.H.G., B. Ghetti, J.R.G., S.G., B. Giordani, J.D.G., J.H.G., R.L.H., L.E.H., E.H., L.S.H., C.M.H., B.T.H., G.A.J., L.-W.J., N.J., J.K., A.K., J.A.K., R.K., E.H.K., N.W.K., J.J.L., A.I.L., A.P.L., O.L.L., W.J.M., D.C. Marson, F.M., D.C. Mash, E.M., W.C.M., S.M.M., A.N.M., A.C.M., M.M., B.L.M., C.A.M., J.W.M., J.E.P., D.P.P., E.P., R.C.P., W.W.P., J.F.Q., M.R., B.R., J.M.R., E.D.R., R.N.R., M.S., L.S.S., W.S., M.L.S., M.A.S., C.D.S., J.A. Sonnen, S.S., R.A.S., R.E.T., J.Q.T., J.C.T., V.M.V., H.V.V., J.P.V., S.W., K.A.W.-B., J.W., R.L.W., L.B.C., B.A.D., D. Beekly, M.I.K., A.J.S., E.M.R., D.A.B., A.M.G., W.A.K., T.M.F., J.L.H., R.M., M.A.P.-V., L.A.F.

Study management and coordination: L.B.C., D. Beekly, D.A.B., J.C.M., T.J.M., A.M.G., D. Blacker, D.W.T., H.H., W.A.K., T.M.F., J.L.H., R.M., M.A.P.-V., L.A.F., G.D.S.

Statistical methods and analysis: A.C.N., G.J., G.W.B., L.-S.W., B.N.V., J.B., P.J.G., R.M.C., R.A.R., M.A.S., K.L.L., E.R.M., J.L.H., M.A.P.-V., L.A.F.

Interpretation of results: A.C.N., G.J., G.W.B., L.-S.W., B.N.V., J.B., P.J.G., R.A.R., M.A.S., K.L.L., E.R.M., M.I.K., A.J.S., E.M.R., D.A.B., J.C.M., T.J.M., A.M.G., D. Blacker, D.W.T., H.H., W.A.K., T.M.F., J.L.H., R.M., M.A.P.-V., L.A.F., G.D.S.

Manuscript writing group: A.C.N., G.J., G.W.B., L.-S.W., B.N.V., J.B., P.J.G., J.L.H., R.M., M.A.P.-V., L.A.F., G.D.S.

Study design: D.A.B., J.C.M., T.J.M., A.M.G., D. Blacker, D.W.T., H.H., W.A.K., T.M.F., J.L.H., R.M., M.A.P.-V., L.A.F., G.D.S.

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Correspondence to Gerard D Schellenberg.

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Competing interests

T.D.B. received licensing fees from and is on the speaker's bureau of Athena Diagnostics, Inc. M.R.F. receives research funding from Bristol-Myers Squibb Company, Danone Research, Elan Pharmaceuticals, Inc., Eli Lilly and Company, Novartis Pharmaceuticals Corporation, OctaPharma AG, Pfizer Inc. and Sonexa Therapeutics, Inc; receives honoraria as scientific consultant from Accera, Inc., Astellas Pharma US Inc., Baxter, Bayer Pharmaceuticals Corporation, Bristol-Myers Squibb, Eisai Medical Research, Inc., GE Healthcare, Medavante, Medivation, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corp., Pfizer, Inc., Prana Biotechnology Ltd., QR Pharma., Inc., the Sanofi-aventis Group and Toyama Chemical Co., Ltd.; and is speaker for Eisai Medical Research, Inc., Forest Laboratories, Pfizer Inc. and Novartis Pharmaceuticals Corporation. A.M.G. has research funding from AstraZeneca, Pfizer and Genentech and has received remuneration for giving talks at Pfizer and Genentech. R.C.P. is on the Safety Monitoring Committee of Pfizer, Inc. (Wyeth) and a consultant to the Safety Monitoring Committee at Janssen Alzheimer's Immunotherapy Program (Elan), to Elan Pharmaceuticals, and to GE Healthcare. R.E.T. is a consultant to Eisai, Japan in the area of Alzheimer's genetics and a shareholder in and consultant to Pathway Genomics, Inc, San Diego, California, USA.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4 and 8 and 9, Supplementary Figures 1 and 2 and Supplementary Note (PDF 885 kb)

Supplementary Table 5

Association Results for SNPs with P<10−4 in the Stage 1 Discovery Meta-Analysis and Joint Analysis (XLS 271 kb)

Supplementary Table 6

Functional SNPs Near Regions with Associations of P<10−4 in the Stage 1 Discovery Meta-analysis and Joint Analysis (XLS 1063 kb)

Supplementary Table 7

Association Results from ADGC Discovery (Stage 1) Analyses for SNPs Highlighted by Previous GWAS Studies (XLS 84 kb)

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Naj, A., Jun, G., Beecham, G. 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).

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