Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Journal name:
Nature Genetics
Volume:
46,
Pages:
989–993
Year published:
DOI:
doi:10.1038/ng.3043
Received
Accepted
Published online

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

At a glance

Figures

  1. Manhattan plot of discovery-phase meta-analyses.
    Figure 1: Manhattan plot of discovery-phase meta-analyses.

    Black font denotes replicated loci from the discovery phase, and gray font denotes loci that did not replicate.

  2. Forest plots describing cohort-level and summary effects from risk profile analyses.
    Figure 2: Forest plots describing cohort-level and summary effects from risk profile analyses.

    Horizontal lines denote 95% confidence intervals.

Accession codes

Referenced accessions

Gene Expression Omnibus

References

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Author information

  1. These authors contributed equally to this work.

    • Mike A Nalls &
    • Nathan Pankratz

Affiliations

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

    • Mike A Nalls,
    • Dena G Hernandez,
    • Margaux F Keller,
    • Sampath Arepalli,
    • Christopher Letson,
    • Connor Edsall,
    • Hannah Pliner &
    • Andrew B Singleton
  2. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Nathan Pankratz
  3. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Christina M Lill &
    • Lars Bertram
  4. Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

    • Christina M Lill
  5. 23andMe, Inc., Mountain View, California, USA.

    • Chuong B Do &
    • Nicholas Eriksson
  6. Reta Lila Weston Institute, University College London Institute of Neurology, Queen Square, London, UK.

    • Dena G Hernandez &
    • John A Hardy
  7. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Mohamad Saad
  8. INSERM, UMR 1043, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, France.

    • Mohamad Saad &
    • Maria Martinez
  9. Paul Sabatier University, Toulouse, France.

    • Mohamad Saad &
    • Maria Martinez
  10. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Anita L DeStefano &
    • Richard H Myers
  11. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Anita L DeStefano
  12. National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA.

    • Anita L DeStefano
  13. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.

    • Eleanna Kara,
    • Jose Bras,
    • Nicholas W Wood &
    • Henry Houlden
  14. Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.

    • Manu Sharma
  15. Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

    • Manu Sharma,
    • Claudia Schulte &
    • Thomas Gasser
  16. deCODE Genetics, Reykjavík, Iceland.

    • Hreinn Stefansson &
    • Kari Stefansson
  17. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.

    • Xinmin Liu &
    • Lorraine N Clark
  18. The Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA.

    • Joseph H Lee,
    • Rong Cheng,
    • Karen Marder &
    • Lorraine N Clark
  19. Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

    • M Arfan Ikram
  20. Department of Radiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

    • M Arfan Ikram
  21. Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

    • M Arfan Ikram
  22. Stanford Prevention Research Center, Stanford University, Stanford, California, USA.

    • John P A Ioannidis
  23. Neuroscience Unit, Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Greece.

    • Georgios M Hadjigeorgiou &
    • Georgia Xiromerisiou
  24. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
  25. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Joel S Perlmutter &
    • Alison Goate
  26. Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Joel S Perlmutter
  27. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Joel S Perlmutter &
    • Alison Goate
  28. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Alison Goate
  29. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Alison Goate
  30. Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York, USA.

    • Karen Marder
  31. Department of Neurology, Columbia University Medical Center, New York, New York, USA.

    • Karen Marder
  32. Department of Psychiatry, Columbia University Medical Center, New York, New York, USA.

    • Karen Marder
  33. The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.

    • Brian Fiske
  34. Neuroscience Center, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.

    • Margaret Sutherland
  35. Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece.

    • Georgia Xiromerisiou
  36. Genome Biology for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

    • Peter Heutink
  37. Epidemiology Branch, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle, North Carolina, USA.

    • Honglei Chen
  38. New York State Department of Health Wadsworth Center, Albany, New York, USA.

    • Haydeh Payami
  39. Sorbonne Université, UPMC Université Paris 06, UM 75, INSERM U1127, Institut du Cerveau et de la Moelle, Paris, France.

    • Alexis Brice
  40. CNRS, UMR 7225, Paris, France.

    • Alexis Brice
  41. Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France.

    • Alexis Brice
  42. Department of Human Genetics, University of Miami School of Medicine, Miami, Florida, USA.

    • William K Scott
  43. School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK.

    • Lars Bertram
  44. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Tatiana Foroud

Consortia

  1. International Parkinson's Disease Genomics Consortium (IPDGC)

  2. A full list of members and affiliations appears in the Supplementary Note.

  3. Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI)

  4. A full list of members and affiliations appears in the Supplementary Note.

  5. 23andMe

  6. A full list of members and affiliations appears in the Supplementary Note.

  7. GenePD

  8. A full list of members and affiliations appears in the Supplementary Note.

  9. NeuroGenetics Research Consortium (NGRC)

  10. A full list of members and affiliations appears in the Supplementary Note.

  11. Hussman Institute of Human Genomics (HIHG)

  12. A full list of members and affiliations appears in the Supplementary Note.

  13. The Ashkenazi Jewish Dataset Investigator

  14. A full list of members and affiliations appears in the Supplementary Note.

  15. Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE)

  16. A full list of members and affiliations appears in the Supplementary Note.

  17. North American Brain Expression Consortium (NABEC)

  18. A full list of members and affiliations appears in the Supplementary Note.

  19. United Kingdom Brain Expression Consortium (UKBEC)

  20. A full list of members and affiliations appears in the Supplementary Note.

  21. Greek Parkinson's Disease Consortium

  22. A full list of members and affiliations appears in the Supplementary Note.

  23. Alzheimer Genetic Analysis Group

  24. A full list of members and affiliations appears in the Supplementary Note.

Contributions

Overall study design: M.A.N., N.P., J.B., A.L.D., B.F., M. Sutherland, J.A.H., N.W.W., T.G., W.K.S., L.B., N.E., T.F. and A.B.S. Design and/or management of the individual studies: M.A.N., C.B.D., J.B., C.S., X.L., J.H.L., R.C., G.M.H., J.S.P., A.G., K.M., A.L.D., R.H.M., L.N.C., J.A.H., P.H., H.C., M. Saad, M. Sharma, M. Sutherland, M.A.I., J.C.B., N.W.W., H.H., H. Payami, H.S., K.S., A.B., W.K.S., T.G., N.E., T.F. and A.B.S. Genotyping: D.G.H., E.K., S.A., C.L., C.E. and H. Pilner. Phenotyping: T.F., G.M.H., J.S.P., K.M., G.X., H.C., N.W.W., H.H., H.S., K.S., A.B., T.F. and W.K.S. Statistical methods and data analysis: M.A.N., N.P., C.M.L., D.G.H., E.K., M. Saad, M. Sharma, C.S., J.P.A.I., M.F.K., M.M., A.L.D., W.K.S., L.B., N.E., T.F. and A.B.S. Writing group: M.A.N., N.P., C.M.L., T.F. and A.B.S. Critical review of the manuscript: M.A.N., N.P., C.M.L., C.B.D., D.G.H., E.K., J.B., C.S., M.F.K., G.M.H., M.M., A.G., B.F., M. Saad, M. Sharma, M. Sutherland, G.X., R.H.M., L.N.C., J.A.H., P.H., H.C., N.W.W., H.H., H. Payami, H. Pilner, H.S., K.S., A.B., W.K.S., T.G., L.B., N.E., T.F., A.B.S. and J.S.P.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

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Supplementary information

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    Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–5.

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