Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy


Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10−3. We found significant previously unidentified signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

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Figure 1: Regional association plots.
Figure 2: Regional association results for the MAPT region of chromosome 17.
Figure 3: Effects of genotypes on gene expression for the MOBP region of chromosome 3 and for the MAPT region of chromosome 17.


  1. 1

    Hoppitt, T. et al. A systematic review of the incidence and prevalence of long-term neurological conditions in the UK. Neuroepidemiology 36, 19–28 (2011).

    Article  Google Scholar 

  2. 2

    Litvan, I. Update on progressive supranuclear palsy. Curr. Neurol. Neurosci. Rep. 4, 296–302 (2004).

    Article  Google Scholar 

  3. 3

    Dickson, D.W., Rademakers, R. & Hutton, M.L. Progressive supranuclear palsy: pathology and genetics. Brain Pathol. 17, 74–82 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Stamelou, M. et al. Rational therapeutic approaches to progressive supranuclear palsy. Brain 133, 1578–1590 (2010).

    Article  Google Scholar 

  5. 5

    McKee, A.C. et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 69, 918–929 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Golbe, L.I. et al. Follow-up study of risk factors in progressive supranuclear palsy. Neurology 47, 148–154 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Baker, M. et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum. Mol. Genet. 8, 711–715 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Cruchaga, C. et al. 5′-upstream variants of CRHR1 and MAPT genes associated with age at onset in progressive supranuclear palsy and cortical basal degeneration. Neurobiol. Dis. 33, 164–170 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Houlden, H. et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 56, 1702–1706 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Sundar, P.D. et al. Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia. Hum. Mol. Genet. 16, 295–306 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Simon-Sanchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308–1312 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Chanock, S.J. et al. Replicating genotype-phenotype associations. Nature 447, 655–660 (2007).

    CAS  Article  Google Scholar 

  14. 14

    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 

  15. 15

    Zody, M.C. et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat. Genet. 40, 1076–1083 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Tian, C. et al. Analysis and application of European genetic substructure using 300 K SNP information. PLoS Genet. 4, e4 (2008).

    Article  Google Scholar 

  17. 17

    Litvan, I. et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47, 1–9 (1996).

    CAS  Article  Google Scholar 

  18. 18

    Osaki, Y. et al. Accuracy of clinical diagnosis of progressive supranuclear palsy. Mov. Disord. 19, 181–189 (2004).

    Article  Google Scholar 

  19. 19

    Duffy, D.L. et al. Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J. Invest. Dermatol. 130, 520–528 (2010).

    CAS  Article  Google Scholar 

  20. 20

    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).

    CAS  Article  Google Scholar 

  21. 21

    Rademakers, R. et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum. Mol. Genet. 14, 3281–3292 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Caffrey, T.M., Joachim, C., Paracchini, S., Esiri, M.M. & Wade-Martins, R. Haplotype-specific expression of exon 10 at the human MAPT locus. Hum. Mol. Genet. 15, 3529–3537 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Myers, A.J. et al. The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol. Dis. 25, 561–570 (2007).

    CAS  Article  Google Scholar 

  24. 24

    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 

  25. 25

    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 

  26. 26

    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 

  27. 27

    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).

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    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  Google Scholar 

  30. 30

    Unterberger, U. et al. Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J. Neuropathol. Exp. Neurol. 65, 348–357 (2006).

    CAS  Article  Google Scholar 

  31. 31

    Hoozemans, J.J.M. et al. The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am. J. Pathol. 174, 1241–1251 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Hoozemans, J.J. et al. Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res. Commun. 354, 707–711 (2007).

    CAS  Article  Google Scholar 

  33. 33

    Jahn, R. & Scheller, R.H. SNAREs–engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7, 631–643 (2006).

    CAS  Article  Google Scholar 

  34. 34

    Wendler, F. & Tooze, S. Syntaxin 6: the promiscuous behaviour of a SNARE protein. Traffic 2, 606–611 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Montague, P., McCallion, A.S., Davies, R.W. & Griffiths, I.R. Myelin-associated oligodendrocytic basic protein: a family of abundant CNS myelin proteins in search of a function. Dev. Neurosci. 28, 479–487 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Scheper, W. & Hoozemans, J.J.M. Endoplasmic reticulum protein quality control in neurodegenerative disease: the good, the bad and the therapy. Curr. Med. Chem. 16, 615–626 (2009).

    CAS  Article  Google Scholar 

  37. 37

    Paschen, W. & Mengesdorf, T. Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease—therapeutic potential. Pharmacol. Ther. 108, 362–375 (2005).

    CAS  Article  Google Scholar 

  38. 38

    Hauw, J.J. et al. Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44, 2015–2019 (1994).

    CAS  Article  Google Scholar 

  39. 39

    Dickson, D.W. et al. Office of rare diseases neuropathologic criteria for corticobasal degeneration. J. Neuropathol. Exp. Neurol. 61, 935–946 (2002).

    CAS  Article  Google Scholar 

  40. 40

    Lee, A.B., Luca, D., Klei, L., Devlin, B. & Roeder, K. Discovering genetic ancestry using spectral graph theory. Genet. Epidemiol. 34, 51–59 (2010).

    CAS  Article  Google Scholar 

  41. 41

    Crossett, A. et al. Using ancestry matching to combine family-based and unrelated samples for genome-wide association studies. Stat. Med. 29, 2932–2945 (2010).

    Article  Google Scholar 

  42. 42

    Tian, C., Plenge, R.M., Ransom, M., Lee, A. & Villoslada, P. Analysis and application of European genetic substructure using 300K SNP information. PLoS Genet. 4, e4 (2008).

    Article  Google Scholar 

  43. 43

    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 

  44. 44

    Luca, D. et al. On the use of general control samples for genome-wide association studies: genetic matching highlights causal variants. Am. J. Hum. Genet. 82, 453–463 (2008).

    CAS  Article  Google Scholar 

  45. 45

    Wu, J., Devlin, B., Ringquist, S., Trucco, M. & Roeder, K. Screen and clean: a tool for identifying interactions in genome-wide association studies. Genet Epidemiol 34, 275–285 (2010).

    PubMed  PubMed Central  Google Scholar 

  46. 46

    Gibbs, J.R. et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 6, e1000952 (2010).

    Article  Google Scholar 

  47. 47

    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 

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We thank the subjects and their families that participated in this study. This work was funded by grants from the CurePSP Foundation, the Peebler PSP Research Foundation and US National Institutes of Health (NIH) grants R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216 (National Institute on Aging (NIA)/NIH), MH057881 and MH077930 (National Institute of Mental Health (NIMH)). Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS08136-4) and the Deutsche Forschungsgemeinschaft (HO 2402/6-1), Prinses Beatrix Fonds (JCvS, 01-0128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals National Health Service Foundation Trust and by a grant from the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Research Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the 'Human Genetic Bank of Patients affected by Parkinson Disease and Parkinsonism' ( of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project no. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute and the Canadian Institute of Health Research. Brain-Net-Germany is supported by the Federal Ministry of Education and Research (BMBF) (01GI0505). R.d.S., A.J.L. and J.A.H. are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. R.d.S. is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. Z.K.W. is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052030 and MCF #90052030) and the gift from C.E. Bolch Jr. and S.B. Bolch (MCF #90052031/PAU #90052). The Mayo Clinic College of Medicine would like to acknowledge M. Baker, R. Crook, M. DeJesus-Hernandez and N. Rutherford for their preparation of samples. P.P. was supported by a grant from the Government of Navarra ('Ayudas para la Realización de Proyectos de Investigación' 2006–2007) and acknowledges the 'Iberian Atypical Parkinsonism Study Group Researchers': M.A. Pastor, M.R. Luquin, M. Riverol, J.A. Obeso and M.C. Rodriguez-Oroz (Department of Neurology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain), M. Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), A. Lopez de Munain, B. Indakoetxea, J. Olaskoaga, J. Ruiz, J. Félix Martí Massó (Servicio de Neurología, Hospital Donostia, San Sebastián, Spain), V. Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), T. Tuñon (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), F. Moreno (Servicio de Neurología, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), A. Alzualde (Neurogenétics Department, Hospital Donostia, San Sebastián, Spain). E.T. wishes to acknowledge the Banco de Tejidos Neurológicos de la Universidad de Barcelona-Hospital Clinic, which provided many tissue samples for the project. We also acknowledge E. Loomis for providing technical support.

The datasets used for older controls were obtained from Database for Genotypes and Phenotypes (dbGap) at Funding support for the 'Genetic Consortium for Late Onset Alzheimer's Disease' was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer's Disease (study accession number: phs000168.v1.p1.) includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer's Disease. Funding support for the 'CIDR Visceral Adiposity Study' (study accession number: phs000169.v1.p1.) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genome-wide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators. Funding support for the Personalized Medicine Research Project (PMRP) was provided through a cooperative agreement (U01HG004608) with the National Human Genome Research Institute (NHGRI), with additional funding from the National Institute for General Medical Sciences (NIGMS). The samples used for PMRP analyses were obtained with funding from Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy grant number D1A RH00025 and Wisconsin Department of Commerce Technology Development Fund contract number TDF FYO10718. Funding support for genotyping, which was performed at Johns Hopkins University, was provided by the NIH (U01HG004438). Assistance with phenotype harmonization and genotype cleaning was provided by the eMERGE Administrative Coordinating Center (U01HG004603) and the National Center for Biotechnology Information (NCBI). The datasets used for the analyses described in this manuscript were obtained from dbGaP at through dbGaP accession number phs000170.v1.p1.

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Co-first authors G.U.H., N.M.M., D.W.D. and P.M.A.S. and senior authors U.M. and G.D.S. contributed equally to this project. G.U.H. and U.M. initiated this study and consortium, drafted the first grant and protocol, coordinated the European sample acquisition and preparation, contributed to data interpretation and contributed to the preparation of the manuscript. N.M.M. conducted the analyses and contributed to the preparation of the manuscript. D.W.D. contributed to study design, data interpretation and preparation of the manuscript. P.M.A.S. contributed in the selection of controls for both phases of the experiment, data quality control, data analysis and content curation for the replication phase custom array. L.-S.W. participated in the initial association analysis, eSNP and pathway analysis and functional annotation of SNPs in the top genes. L.K. participated in genotype quality control and analysis. R.R. and R.d.S. participated in study design, sample preparation and revising the manuscript for content. I. Litvan, D.E.R., J.C.V.S., P.H., Z.K.W., R.J.U., J.V., H.I.H., R.G.G., W.M., S.G., E.T., B.B., P.P. and the PSP Genetics Study Group (R.L.A., E.A., A.A., M.A., S.E.A., J.A., T.B., S.B., D.B., T.D.B., N.B., A.J.W.B., Y.B., A.B., H.B., M.C., W.Z.C., R.C., C.C., P.P.D., J.G.D., L.D.K., R.D., A. Durr, S.E., G.F., N.A.F., R.F., M.P.F., C.G., D.R.G., T.G., M. Gearing, E.T.G., B.G., N.R.G.R., M. Grossman, D.A.H., L.H., M.H., J.J., J.L.J., A.K., H.A.K., I. Leber, V.M.L., A.P.L., K.L., C. Mariani, E.M., L.A.M., C.A.M., N.M., B.L.M., B.M., J.C.M., H.R.M., C. Morris, S.S.O., W.H.O., D.O., A.P., R.P., G.P., S.P.B., W.P., A. Rabano, A. Rajput, S.G.R., G.R., S.R., J.D.R., O.A.R., M.N.R., G.S., W.W.S., K. Seppi, L.S.M., S.S., K. Srulijes, P.S.G., M.S., D.G.S., S.T., W.W.T., C. Trenkwalder, C. Troakes, J.Q.T., J.C.T., V.M.V., J.P.G.V., G.K.W., C.L.W., P.W., C.Z. and A.L.Z.) participated in characterization, preparation and contribution of samples from individuals with PSP. L.B.C. coordinated the project, sample acquisition and selection and managed phenotypes. M.R.H. conducted eSNP and pathway analysis. A. Dillman performed mRNA expression experiments in human brain. M.P.v.d.B. and D.G.H. performed mRNA expression experiments in human brain and contributed to the design of eQTL experiments. J.R.G. performed computational and statistical analysis of the eQTL data and contributed to the design of eQTL experiments. M.R.C. and A.B.S. were responsible for overall supervision, design and analysis of eQTL experiments. J.C.V.S., M.J.F., L.I.G., J.H. and A.J.L. participated in study design and data analysis discussions. C.-E.Y. and T.R. participated in the initial design of experiments. B.D. supervised analyses and contributed to the writing of the manuscript. H.H. supervised genotyping and platform and sample selection, participated in analyses and reviewed the manuscript. G.D.S. led the consortium, supervised study design, coordinated the US sample acquisition and preparation, contributed to data interpretation and wrote and coordinated assembly of the manuscript.

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Correspondence to Ulrich Müller or Gerard D Schellenberg.

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A list of members appears at the end of the paper.

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Supplementary Tables 1–6 and 8–10 and Supplementary Figures 1–5. (PDF 701 kb)

Supplementary Table 7

Location and functional consequence of SNPs in genes from the PSP GWAS signals (XLS 54 kb)

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Höglinger, G., Melhem, N., Dickson, D. et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43, 699–705 (2011).

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