Abstract

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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References

  1. 1.

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

  2. 2.

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

  3. 3.

    , & Progressive supranuclear palsy: pathology and genetics. Brain Pathol. 17, 74–82 (2007).

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

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

  8. 8.

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

  9. 9.

    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).

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

    , , & Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

  15. 15.

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

  16. 16.

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

  17. 17.

    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).

  18. 18.

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

  19. 19.

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

  20. 20.

    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).

  21. 21.

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

  22. 22.

    , , , & Haplotype-specific expression of exon 10 at the human MAPT locus. Hum. Mol. Genet. 15, 3529–3537 (2006).

  23. 23.

    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).

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

    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).

  28. 28.

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

  29. 29.

    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).

  30. 30.

    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).

  31. 31.

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

  32. 32.

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

  33. 33.

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

  34. 34.

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

  35. 35.

    , , & Myelin-associated oligodendrocytic basic protein: a family of abundant CNS myelin proteins in search of a function. Dev. Neurosci. 28, 479–487 (2006).

  36. 36.

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

  37. 37.

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

  38. 38.

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

  39. 39.

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

  40. 40.

    , , , & Discovering genetic ancestry using spectral graph theory. Genet. Epidemiol. 34, 51–59 (2010).

  41. 41.

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

  42. 42.

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

  43. 43.

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

  44. 44.

    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).

  45. 45.

    , , , & Screen and clean: a tool for identifying interactions in genome-wide association studies. Genet Epidemiol 34, 275–285 (2010).

  46. 46.

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

  47. 47.

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

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Acknowledgements

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' (http://www.parkinson.it/dnabank.html) 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 http://www.ncbi.nlm.nih.gov/gap/. 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 http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000170.v1.p1.

Author information

Author notes

    • Günter U Höglinger
    • , Nadine M Melhem
    • , Dennis W Dickson
    • , Patrick M A Sleiman
    • , Ulrich Müller
    •  & Gerard D Schellenberg

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurology, Philipps-Universität, Marburg, Germany.

    • Günter U Höglinger
  2. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Nadine M Melhem
    • , Lambertus Klei
    •  & Bernie Devlin
  3. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

    • Dennis W Dickson
    •  & Rosa Rademakers
  4. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Patrick M A Sleiman
    •  & Hakon Hakonarson
  5. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Li-San Wang
    • , Laura B Cantwell
    • , Mi Ryung Han
    •  & Gerard D Schellenberg
  6. Reta Lila Weston Institute, University College London (UCL) Institute of Neurology, London, UK.

    • Rohan de Silva
    • , Jana Vandrovcova
    • , J Raphael Gibbs
    • , Dena G Hernandez
    • , John Hardy
    •  & Andrew J Lees
  7. Department of Neurology, Division of Movement Disorders, University of Louisville, Louisville, Kentucky, USA.

    • Irene Litvan
  8. Department of Neurology, University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA.

    • David E Riley
  9. Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • John C van Swieten
  10. Department of Clinical Genetics, Vrije Universiteit (VU) Medical Center, Section Medical Genomics, Amsterdam, The Netherlands.

    • Peter Heutink
  11. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.

    • Zbigniew K Wszolek
    •  & Ryan J Uitti
  12. Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.

    • Howard I Hurtig
    •  & Rachel G Gross
  13. Center of Neurology, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

    • Walter Maetzler
  14. German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.

    • Walter Maetzler
  15. Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy.

    • Stefano Goldwurm
  16. Neurology Service, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.

    • Eduardo Tolosa
  17. Department of Medical and Surgical Sciences, Institute of Neurology, University of Brescia, Brescia, Italy.

    • Barbara Borroni
  18. CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.

    • Pau Pastor
  19. Neurogenetics laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain.

    • Pau Pastor
  20. Department of Neurology, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain.

    • Pau Pastor
  21. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Allissa Dillman
    • , J Raphael Gibbs
    • , Mark R Cookson
    • , Dena G Hernandez
    •  & Andrew B Singleton
  22. Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.

    • Marcel P van der Brug
  23. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Matthew J Farrer
  24. Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

    • Chang-En Yu
  25. Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.

    • Chang-En Yu
  26. Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.

    • Lawrence I Golbe
  27. Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.

    • Tamas Revesz
    •  & Andrew J Lees
  28. Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany.

    • Ulrich Müller
  29. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.

    • Roger L Albin
  30. Geriatrics Research, Education, and Clinical Center, Veterans Affairs (VA) Ann Arbor Health System, Ann Arbor, Michigan, USA.

    • Roger L Albin
  31. CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.

    • Elena Alonso
  32. Neurogenetics Laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain.

    • Elena Alonso
  33. Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.

    • Angelo Antonini
    • , Margherita Canesi
    • , Roberto Cilia
    • , Claudio Mariani
    • , Nicoletta Meucci
    • , Gianni Pezzoli
    • , Giorgio Sacilotto
    • , Silvana Tesei
    •  & Anna L Zecchinelli
  34. Department for Parkinson's Disease, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) San Camillo, Venice, Italy.

    • Angelo Antonini
  35. Institute of Legal Medicine, University of Würzburg, Würzburg, Germany.

    • Manuela Apfelbacher
  36. Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Steven E Arnold
  37. Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Campus Cantoblanco, Universidad Autonoma de Madrid, Madrid, Spain.

    • Jesus Avila
  38. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

    • Thomas G Beach
  39. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Sherry Beecher
    • , Evan T Geller
    • , Virginia M Lee
    • , John Q Trojanowski
    •  & Vivianna M Van Deerlin
  40. Center of Neurology, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany.

    • Daniela Berg
    • , Thomas Gasser
    •  & Karin Srulijes
  41. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.

    • Thomas D Bird
  42. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Hudding University Hospital, Stockholm, Sweden.

    • Nenad Bogdanovic
  43. Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Agnita J W Boon
    • , Wang Zheng Chiu
    •  & Laura Donker Kaat
  44. Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.

    • Yvette Bordelon
  45. Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie, Paris, France.

    • Alexis Brice
    • , Alexandra Durr
    •  & Isabelle Leber
  46. Institut National de la Santé et de la Recherche Médicale, Paris, France.

    • Alexis Brice
    • , Alexandra Durr
    •  & Isabelle Leber
  47. Centre National de la Recherche Scientifique, Paris, France.

    • Alexis Brice
    • , Alexandra Durr
    •  & Isabelle Leber
  48. Institute of Neurology, Medical University Vienna, Vienna, Austria.

    • Herbert Budka
  49. Dipartimento di Scienze Neurologiche e Psichiatriche, Sapienza Università di Roma, Rome, Italy.

    • Carlo Colosimo
    • , Giovanni Fabbrini
    •  & Donatella Ottaviani
  50. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

    • Peter P De Deyn
    •  & Sebastiaan Engelborghs
  51. Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain.

    • Justo García de Yebenes
  52. Wien Center for Alzheimer's Disease and Memory Disorders, Mt. Sinai Medical Center, Miami Beach, Florida, USA.

    • Ranjan Duara
  53. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

    • NiCole A Finch
    •  & Owen A Ross
  54. Centre for Neuroscience, Flinders University and Australian Brain Bank Network, Victoria, Australia.

    • Robyn Flook
  55. C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Matthew P Frosch
  56. Neurology Service, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.

    • Carles Gaig
  57. Department of Neurosciences, University of California San Diego, La Jolla, California, USA.

    • Douglas R Galasko
    •  & Eliezer Masliah
  58. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Marla Gearing
  59. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Bernardino Ghetti
    •  & Salvatore Spina
  60. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.

    • Neill R Graff-Radford
  61. Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.

    • Murray Grossman
  62. Department of Neurological Sciences, Rush University, Chicago, Illinois, USA.

    • Deborah A Hall
  63. Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.

    • Lili-Naz Hazrati
    •  & Peter St. George-Hyslop
  64. Department of Neurology, Philipps University, Marburg, Germany.

    • Matthias Höllerhage
    • , Jens C Möller
    • , Wolfgang H Oertel
    • , Gesine Respondek
    •  & Maria Stamelou
  65. Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.

    • Joseph Jankovic
  66. Department of Neurology, Emory University, Atlanta, Georgia, USA.

    • Jorge L Juncos
  67. Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.

    • Anna Karydas
    • , Bruce L Miller
    •  & William W Seeley
  68. Institut für Neuropathologie, Ludwig-Maximilians-Universität and Brain Net Germany, Munich, Germany.

    • Hans A Kretzschmar
    •  & Sigrun Roeber
  69. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • Andrew P Lieberman
  70. Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • Kelly E Lyons
    •  & Rajesh Pahwa
  71. Department of Pathology, University of California San Diego, La Jolla, California, USA.

    • Eliezer Masliah
  72. Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.

    • Luke A Massey
    • , Sean S O'Sullivan
    •  & Laura Silveira-Moriyama
  73. Victorian Brain Bank Network, Mental Health Research Institute, Victoria, Australia.

    • Catriona A McLean
  74. Department of Neurology, Georg-August University, Goettingen, Germany.

    • Brit Mollenhauer
  75. Paracelsus-Elena-Klinik, University of Goettingen, Kassel, Germany.

    • Brit Mollenhauer
    •  & Claudia Trenkwalder
  76. Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Department of Neurology, School of Medicine, Cardiff University, Cardiff, UK.

    • Huw R Morris
  77. Newcastle Brain Tissue Resource, Newcastle University, Institute for Ageing and Health, Newcastle upon Tyne, UK.

    • Chris Morris
  78. Department of Medical and Surgical Sciences, Institute of Neurology, University of Brescia, Brescia, Italy.

    • Alessandro Padovani
  79. Neurodegeneration and Mental Health Research Group, Faculty of Human and Medical Sciences, University of Manchester, Manchester, UK.

    • Stuart Pickering-Brown
  80. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

    • Werner Poewe
    • , Klaus Seppi
    •  & Gregor K Wenning
  81. Department of Neuropathology and Tissue Bank, Fundación Centro Investigación Enfermedades Neurológicas (CIEN), Instituto de Salud Carlos III, Madrid, Spain.

    • Alberto Rabano
  82. Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatchewan, Canada.

    • Alex Rajput
  83. Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Stephen G Reich
  84. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, UCL, London, UK.

    • Jonathan D Rohrer
    •  & Martin N Rossor
  85. Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

    • Peter St. George-Hyslop
  86. Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • David G Standaert
  87. Human Brain and Spinal Fluid Resource Center, Veterans Affairs West Los Angeles Healthcare Center, Los Angeles, California, USA.

    • Wallace W Tourtellotte
  88. Department of Clinical Neuroscience, MRC Centre for Neurodegeneration Research, King's College London, London, UK.

    • Claire Troakes
  89. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Juan C Troncoso
  90. Department of Pathology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.

    • Jean Paul G Vonsattel
  91. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Charles L White
  92. Institute of Human Genetics, Justus-Liebig University, Giessen, Germany.

    • Pia Winter
  93. Rancho Los Amigos National Rehabilitation Center, University of Southern California, Downey, California, USA.

    • Chris Zarow

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  1. PSP Genetics Study Group

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

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ulrich Müller or Gerard D Schellenberg.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–6 and 8–10 and Supplementary Figures 1–5.

Excel files

  1. 1.

    Supplementary Table 7

    Location and functional consequence of SNPs in genes from the PSP GWAS signals

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DOI

https://doi.org/10.1038/ng.859

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