Abstract

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

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Acknowledgements

We thank the subjects involved in this study whose contribution made this work possible. This work used samples and clinical data from the US National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds). This work was supported in part by the Intramural Research Programs of the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the National Institute of Environmental Health Sciences, the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services; project numbers Z01 AG000949-02 and Z01-ES101986. The KORA research platform (KORA: Cooperative Research in the Region of Augsburg; ) was initiated and financed by the Forschungszentrum für Umwelt und Gesundheit (GSF), which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria.

The study was additionally funded by the German National Genome Network (NGFNplus #01GS08134; German Ministry for Education and Research) and in addition by the German Federal Ministry of Education and Research (BMBF) NGFN (01GR0468). This work also was supported by the National Institutes of Health NINDS P30NS05710 (Neuroscience Blueprint Grant) and Clinical Sciences Translational Award RR024992 to Washington University in St. Louis and the Greater St. Louis Chapter of the American Parkinson Disease Association. Authors received support from the Medical Research Council, UK.

Author information

Author notes

    • Javier Simón-Sánchez
    • , Claudia Schulte
    • , Jose M Bras
    •  & Manu Sharma

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Javier Simón-Sánchez
    • , Jose M Bras
    • , J Raphael Gibbs
    • , Sonja W Scholz
    • , Dena G Hernandez
    • , Monica Federoff
    • , Michael A Nalls
    • , Mark R Cookson
    • , Bryan J Traynor
    • , Sampath Arepalli
    • , Ryan Zonozi
    • , Marcel van der Brug
    •  & Andrew B Singleton
  2. Department of Clinical Genetics Section of Medical Genomics VU Medical Center De Boelelaan Amsterdam, The Netherlands.

    • Javier Simón-Sánchez
  3. Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases, Tübingen, Germany.

    • Claudia Schulte
    • , Manu Sharma
    • , Daniela Berg
    • , Rejko Krüger
    •  & Thomas Gasser
  4. Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.

    • Jose M Bras
  5. Department of Molecular Neuroscience and Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.

    • J Raphael Gibbs
    • , Coro Paisan-Ruiz
    • , Sonja W Scholz
    • , Dena G Hernandez
    • , Henry Houlden
    • , Nick W Wood
    •  & John A Hardy
  6. Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

    • Peter Lichtner
  7. Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Luebeck, Germany.

    • Christine Klein
  8. Department of Psychiatry and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Alison Goate
    • , Joel Perlmutter
    •  & Brad A Racette
  9. Department of Medical Genetics, Institute of Human Genetics, University of Tübingen, Tübingen, Germany.

    • Michael Bonin
    •  & Olaf Riess
  10. Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

    • Thomas Illig
    •  & Christian Gieger
  11. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.

    • Michael Steffens
  12. Movement Disorders Center, University of Florida, Gainesville, Florida, USA.

    • Michael S Okun
    • , Kelly D Foote
    •  & Hubert H Fernandez
  13. Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität Kiel, Germany.

    • Stefan Schreiber
  14. Department of Molecular and Human Genetics, Baylor College of Medicine, Texas, USA.

    • Katrina Gwinn
  15. Department of Neuroscience, The Scripps Research Institute, Scripps, Florida, USA.

    • Marcel van der Brug
  16. Parkinson's disease clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

    • Grisel Lopez
  17. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

    • Stephen J Chanock
    • , Arthur Schatzkin
    •  & Yikyung Park
  18. AARP, Washington, DC, USA.

    • Albert Hollenbeck
  19. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, North Carolina, USA.

    • Jianjun Gao
    •  & Honglei Chen
  20. Departments of Neurology, Radiology, Neurosurgery, Pharmacology, Kinesiology and Bioengineering, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.

    • Xuemei Huang
  21. Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität Kiel, Kiel, Germany.

    • Delia Lorenz
    •  & Günther Deuschl

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Contributions

J.S.-S. performed genotyping, conducted statistical analyses and participated in writing the manuscript. C.S. conducted statistical analyses and participated in writing the manuscript. J.M.B. performed genotyping, conducted statistical analyses and participated in writing the manuscript. M.S. conducted statistical analyses and participated in writing the manuscript. J.R.G. conducted statistical analyses. D.B. contributed samples and collected phenotypic data. C.P.-R. contributed samples and performed genotyping. P.L. performed genotyping. S.W.S. performed genotyping and conducted statistical analyses. D.G.H. performed genotyping. R.K. contributed samples and collected phenotypic data. M.F. performed genotyping. C.K. contributed samples and collected phenotypic data. A.G. contributed samples. J.P. contributed samples and collected phenotypic data. M.B. performed genotyping. M.A.N. conducted statistical analyses. T.I. contributed samples and collected phenotypic data. C.G. contributed samples and collected phenotypic data. H.H. contributed samples and collected phenotypic data. M.S. conducted statistical analyses. M.S.O. contributed samples and collected phenotypic data. B.A.R. contributed samples and collected phenotype data. M.C. performed eQTL analysis. K.D.F. contributed samples. H.H.F. contributed samples. B.J.T. performed eQTL analysis. S.S. contributed samples and collected phenotypic data. S.A. performed genotyping. R.Z. performed genotyping. K.G. contributed samples and collected phenotypic data. M.v.d.B. performed eQTL analysis. G.L. contributed samples. S.J.C. contributed control samples. A.S. contributed samples. Y.P. contributed samples. A.H. contributed samples. J.G. contributed samples. X.H. contributed samples. N.W.W. contributed samples and collected phenotypic data. D.L. contributed samples and collected phenotypic data. G.D. contributed samples and collected phenotypic data. H.C. contributed samples and collected phenotypic data. O.R. obtained funding and supervised genotyping. J.A.H. contributed samples and collected phenotypic data. A.B.S. designed and supervised the study, contributed samples and collected phenotypic data and participated in writing the manuscript. T.G. designed and supervised the study, contributed samples and collected phenotypic data and participated in writing the manuscript. All authors participated in critical revision of the manuscript for intellectual content.

Corresponding authors

Correspondence to Andrew B Singleton or Thomas Gasser.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Methods, Supplementary Figures 1–8 and Supplementary Tables 1–6.

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DOI

https://doi.org/10.1038/ng.487

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