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Genome-wide association study reveals genetic risk underlying Parkinson's disease

Nature Genetics volume 41, pages 1308–1312 (2009)Cite this article

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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Figure 1: Graphical representation of P values in stage I and stage II.
Figure 2: Association results and recombination rates.
Figure 3: Expression quantitative trait loci across the MAPT locus measured in 133 human frontal cortex samples.

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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.

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Author notes

  1. Javier Simón-Sánchez, Claudia Schulte, Jose M Bras and Manu Sharma: These authors contributed equally to this work.

Authors and 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, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, 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

Authors
  1. Javier Simón-Sánchez
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  2. Claudia Schulte
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  3. Jose M Bras
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  40. Nick W Wood
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  43. Honglei Chen
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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.

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Supplementary Note, Supplementary Methods, Supplementary Figures 1–8 and Supplementary Tables 1–6. (PDF 3473 kb)

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Simón-Sánchez, J., Schulte, C., Bras, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 41, 1308–1312 (2009). https://doi.org/10.1038/ng.487

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