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Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

Abstract

The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10−5) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81–0.90, P = 7.5 × 10−9 for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14–1.29, P = 3.7 × 10−9 for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of β amyloid (Aβ) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.

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Figure 1: Schematic overview of CLU and LD patterns at the CLU locus.
Figure 2: Schematic overview of CR1 and LD patterns at the CR1 locus.

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References

  1. Small, S.A. & Duff, K. Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron 60, 534–542 (2008).

    Article  CAS  Google Scholar 

  2. Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  Google Scholar 

  3. Campion, D. et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am. J. Hum. Genet. 65, 664–670 (1999).

    Article  CAS  Google Scholar 

  4. Farrer, L.A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. J. Am. Med. Assoc. 278, 1349–1356 (1997).

    Article  CAS  Google Scholar 

  5. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).

    Article  Google Scholar 

  6. Ashford, J.W. & Mortimer, J.A. Non-familial Alzheimer's disease is mainly due to genetic factors. J. Alzheimers Dis. 4, 169–177 (2002).

    Article  Google Scholar 

  7. Bertram, L., McQueen, M.B., Mullin, K., Blacker, D. & Tanzi, R.E. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39, 17–23 (2007).

    Article  CAS  Google Scholar 

  8. Reiman, E.M. et al. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron 54, 713–720 (2007).

    Article  CAS  Google Scholar 

  9. 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 

  10. 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).

    Article  CAS  Google Scholar 

  11. Beecham, G.W. et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am. J. Hum. Genet. 84, 35–43 (2009).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. Butler, A.W. et al. Meta-analysis of linkage studies for Alzheimer's disease-A web resource. Neurobiol. Aging 30, 1037–1047 (2009).

    Article  Google Scholar 

  14. Roheim, P.S., Carey, M., Forte, T. & Vega, G.L. Apolipoproteins in human cerebrospinal fluid. Proc. Natl. Acad. Sci. USA 76, 4646–4649 (1979).

    Article  CAS  Google Scholar 

  15. May, P.C. & Finch, C.E. Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration. Trends Neurosci. 15, 391–396 (1992).

    Article  CAS  Google Scholar 

  16. May, P.C. et al. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron 5, 831–839 (1990).

    Article  CAS  Google Scholar 

  17. Calero, M. et al. Apolipoprotein J (clusterin) and Alzheimer's disease. Microsc. Res. Tech. 50, 305–315 (2000).

    Article  CAS  Google Scholar 

  18. Ghiso, J. et al. The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem. J. 293, 27–30 (1993).

    Article  CAS  Google Scholar 

  19. Zlokovic, B.V. et al. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. Proc. Natl. Acad. Sci. USA 93, 4229–4234 (1996).

    Article  CAS  Google Scholar 

  20. DeMattos, R.B. et al. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 99, 10843–10848 (2002).

    Article  CAS  Google Scholar 

  21. DeMattos, R.B. et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 41, 193–202 (2004).

    Article  CAS  Google Scholar 

  22. Bell, R.D. et al. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J. Cereb. Blood Flow Metab. 27, 909–918 (2007).

    Article  CAS  Google Scholar 

  23. Holtzman, D.M. In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. J. Mol. Neurosci. 23, 247–254 (2004).

    Article  CAS  Google Scholar 

  24. Lambert, J.C. & Amouyel, P. Genetic heterogeneity of Alzheimer's disease: complexity and advances. Psychoneuroendocrinology 32, S62–S70 (2007).

    Article  CAS  Google Scholar 

  25. Holtzman, D.M. et al. Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. J. Clin. Invest. 103, R15–R21 (1999).

    Article  CAS  Google Scholar 

  26. Iida, K., Mornaghi, R. & Nussenzweig, V. Complement receptor (CR1) deficiency in erythrocytes from patients with systemic lupus erythematosus. J. Exp. Med. 155, 1427–1438 (1982).

    Article  CAS  Google Scholar 

  27. Song, W.C., Sarrias, M.R. & Lambris, J.D. Complement and innate immunity. Immunopharmacology 49, 187–198 (2000).

    Article  CAS  Google Scholar 

  28. Khera, R. & Das, N. Complement receptor 1: disease associations and therapeutic implications. Mol. Immunol. 46, 761–772 (2009).

    Article  CAS  Google Scholar 

  29. Webster, S., Bradt, B., Rogers, J. & Cooper, N. Aggregation state-dependent activation of the classical complement pathway by the amyloid beta peptide. J. Neurochem. 69, 388–398 (1997).

    Article  CAS  Google Scholar 

  30. Rogers, J. et al. Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol. Aging 27, 1733–1739 (2006).

    Article  CAS  Google Scholar 

  31. Kuo, Y.M. et al. Amyloid-beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochem. Biophys. Res. Commun. 268, 750–756 (2000).

    Article  CAS  Google Scholar 

  32. Zhou, J., Fonseca, M.I., Pisalyaput, K. & Tenner, A.J. Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease. J. Neurochem. 106, 2080–2092 (2008).

    Article  CAS  Google Scholar 

  33. Wyss-Coray, T. et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl. Acad. Sci. USA 99, 10837–10842 (2002).

    Article  CAS  Google Scholar 

  34. Donnelly, P. Progress and challenges in genome-wide association studies in humans. Nature 456, 728–731 (2008).

    Article  CAS  Google Scholar 

  35. Maher, B. Personal genomes: The case of the missing heritability. Nature 456, 18–21 (2008).

    Article  CAS  Google Scholar 

  36. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. advance online publication, doi:10.1038/ng.440 (6 September 2009).

  37. Heath, S.C. et al. Investigation of the fine structure of European populations with applications to disease association studies. Eur. J. Hum. Genet. 16, 1413–1429 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Breslow, N.E., Day, N.E., Halvorsen, K.T., Prentice, R.L. & Sabai, C. Estimation of multiple relative risk functions in matched case-control studies. Am. J. Epidemiol. 108, 299–307 (1978).

    Article  CAS  Google Scholar 

  40. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  41. Tregouet, D.A. & Tiret, L. Cox proportional Hazards survival regression in haplotype-based association analysis using the stochastic-EM algorithm. Eur. J. Hum. Genet. 12, 971–974 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

The work was made possible by the generous participation of the control subjects, the subjects with Alzheimer's disease, and their families. We thank A. Boland (Centre National de Génotypage) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Génotypage.

The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l'Education Nationale, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/Inserm 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai.

Belgium sample collection: the Antwerp site (CVB) was in part supported by the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be/) and the Biobank of the Institute Born-Bunge; the Special Research Fund of the University of Antwerp; the Fund for Scientific Research-Flanders (FWO-V); the Foundation for Alzheimer Research (SAO-FRMA); and the Interuniversity Attraction Poles (IAP) program P6/43 of the Belgian Federal Science Policy Office, Belgium; K.S. is a postdoctoral fellow and K.B. a PhD fellow of the FWO-V.

Finnish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration.

Italian sample collection: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by a grant from the Italian ministry of Health (RFPS-2006-7-334858). The Milan site was supported by a grant from the 'fondazione Monzino'. We appreciate the expert contribution of C. Romano.

Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III) and an institutional grant of the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa. We thank I. Sastre and A. Martínez-García for the preparation and control of the DNA collection and P. Gil and P. Coria for their cooperation in the recruitment of cases and controls. We are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help.

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Project conception, design, management. J.-C.L., M.L., P.A. Phenotype collection, data management. France: D.C., B.T., L.L., C.B., F.Pasquier, N.F., P.B.-G., O.H., C.L., C.D., C.J., T.L., D.H., K.R., H.B., J.-F.D., C.T., A.A. Belgium: K.S., K.B., S.E., P.D.D., C.V.B. Finland: M.H., S.Helisalmi, H.S. Italy: E.P., P.Bosco, M.M., F.Panza, B.N., P.Bossù, P.P., G.A., D.S., D.G., F.L. Spain: O.C., M.J.B., I.M., A.F., M.M.d.P., V.A. Genome-wide, validation genotyping. S.Heath., D.Z., I.G. Data analysis: J.-C.L., S.Heath., G.E., M.L., P.A. Writing group: J.-C.L., S.Heath., M.L., P.A.

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Correspondence to Philippe Amouyel.

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Lambert, JC., Heath, S., Even, G. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41, 1094–1099 (2009). https://doi.org/10.1038/ng.439

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