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

Nature Genetics 46, 989–993 (2014) | Download Citation

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Abstract

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.

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Acknowledgements

We would like to thank all of the subjects who donated their time and biological samples to be a part of this study. For funding details and additional acknowledgments, please see the Supplementary Note.

Author information

    • Mike A Nalls
    •  & Nathan Pankratz

    These authors contributed equally to this work.

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)

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

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

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

  3. 23andMe

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

  4. GenePD

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

  5. NeuroGenetics Research Consortium (NGRC)

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

  6. Hussman Institute of Human Genomics (HIHG)

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

  7. The Ashkenazi Jewish Dataset Investigator

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

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

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

  9. North American Brain Expression Consortium (NABEC)

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

  10. United Kingdom Brain Expression Consortium (UKBEC)

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

  11. Greek Parkinson's Disease Consortium

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

  12. Alzheimer Genetic Analysis Group

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

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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 interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andrew B Singleton.

Supplementary information

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DOI

https://doi.org/10.1038/ng.3043

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