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

Nature Genetics volume 46, pages 989–993 (2014)Cite this article

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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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Figure 1: Manhattan plot of discovery-phase meta-analyses.
Figure 2: Forest plots describing cohort-level and summary effects from risk profile analyses.

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References

  1. Lill, C.M. et al. Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database. PLoS Genet. 8, e1002548 (2012).

    Article  CAS  Google Scholar 

  2. Do, C.B. et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet. 7, e1002141 (2011).

    Article  CAS  Google Scholar 

  3. International Parkinson Disease Genomics Consortium. 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).

  4. International Parkinson's Disease Genomics Consortium (IPDGC) & Wellcome Trust Case Control Consortium 2 (WTCCC2). A two-stage meta-analysis identifies several new loci for Parkinson's disease. PLoS Genet. 7, e1002142 (2011).

  5. Edwards, T.L. et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet. 74, 97–109 (2010).

    Article  CAS  Google Scholar 

  6. Pankratz, N. et al. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum. Genet. 124, 593–605 (2009).

    Article  CAS  Google Scholar 

  7. Pankratz, N. et al. Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. Ann. Neurol. 71, 370–384 (2012).

    Article  CAS  Google Scholar 

  8. Simón-Sánchez, J. et al. Genome-wide association study confirms extant PD risk loci among the Dutch. Eur. J. Hum. Genet. 19, 655–661 (2011).

    Article  Google Scholar 

  9. Hamza, T.H. et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat. Genet. 42, 781–785 (2010).

    Article  CAS  Google Scholar 

  10. Liu, X. et al. Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. BMC Med. Genet. 12, 104 (2011).

    Article  CAS  Google Scholar 

  11. Hernandez, D.G. et al. Genome wide assessment of young onset Parkinson's disease from Finland. PLoS ONE 7, e41859 (2012).

    Article  CAS  Google Scholar 

  12. Pihlstrøm, L. et al. Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiol. Aging 34, 1708.e7–13 (2013).

    Article  Google Scholar 

  13. Sharma, M. et al. Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology 79, 659–667 (2012).

    Article  Google Scholar 

  14. Saad, M. et al. Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population. Hum. Mol. Genet. 20, 615–627 (2011).

    Article  Google Scholar 

  15. Satake, W. et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet. 41, 1303–1307 (2009).

    Article  CAS  Google Scholar 

  16. Elbaz, A. et al. Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann. Neurol. 69, 778–792 (2011).

    Article  CAS  Google Scholar 

  17. Psaty, B.M. et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ. Cardiovasc. Genet. 2, 73–80 (2009).

    Article  Google Scholar 

  18. MacLeod, D.A. et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77, 425–439 (2013).

    Article  CAS  Google Scholar 

  19. Keller, M.F. et al. Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Hum. Mol. Genet. 21, 4996–5009 (2012).

    Article  CAS  Google Scholar 

  20. Wei, Z. et al. Large sample size, wide variant spectrum, and advanced machine-learning technique boost risk prediction for inflammatory bowel disease. Am. J. Hum. Genet. 92, 1008–1012 (2013).

    Article  CAS  Google Scholar 

  21. Willems, S.M., Mihaescu, R., Sijbrands, E.J.G., van Duijn, C.M. & Janssens, A.C.J.W. A methodological perspective on genetic risk prediction studies in type 2 diabetes: recommendations for future research. Curr. Diab. Rep. 11, 511–518 (2011).

    Article  Google Scholar 

  22. Morrison, A.C. et al. Whole-genome sequence–based analysis of high-density lipoprotein cholesterol. Nat. Genet. 45, 899–901 (2013).

    Article  CAS  Google Scholar 

  23. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  24. de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).

    Article  CAS  Google Scholar 

  25. van der Walt, J.M. et al. Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. Am. J. Hum. Genet. 74, 1121–1127 (2004).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  27. Hofman, A. et al. The Rotterdam Study: 2012 objectives and design update. Eur. J. Epidemiol. 26, 657–686 (2011).

    Article  Google Scholar 

  28. Ton, T.G. et al. Post hoc Parkinson's disease: identifying an uncommon disease in the Cardiovascular Health Study. Neuroepidemiology 35, 241–249 (2010).

    Article  CAS  Google Scholar 

  29. Ikram, M.A. et al. Genomewide association studies of stroke. N. Engl. J. Med. 360, 1718–1728 (2009).

    Article  CAS  Google Scholar 

  30. Eriksson, N. et al. Genetic variant sassociated with breast size also influence breast cancer risk. BMC Med. Genet. 13, 53 (2012).

    Article  CAS  Google Scholar 

  31. Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G.R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

    Article  CAS  Google Scholar 

  32. Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    Article  CAS  Google Scholar 

  33. Han, B. & Eskin, E. Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am. J. Hum. Genet. 88, 586–598 (2011).

    Article  CAS  Google Scholar 

  34. Grove, M.L. et al. Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. PLoS ONE 8, e68095 (2013).

    Article  CAS  Google Scholar 

  35. Ripatti, S. et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376, 1393–1400 (2010).

    Article  Google Scholar 

  36. Hernandez, D.G. et al. Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum. Mol. Genet. 20, 1164–1172 (2011).

    Article  CAS  Google Scholar 

Download references

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

Author notes

  1. Mike A Nalls, Nathan Pankratz and Tatiana Foroud: These authors contributed equally to this work.

Authors and 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. Department of Neurology, Neuroscience Unit, Faculty of Medicine, University of Thessaly, Larissa, Greece

    Georgios M Hadjigeorgiou & Georgia Xiromerisiou

  24. Department of Medicine, Cardiovascular Health Research Unit, 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. Department of Genetics and Cytogenetics, Pitié-Salpêtrière Hospital, 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

Authors
  1. Mike A Nalls
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  2. Nathan Pankratz
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  3. Christina M Lill
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  4. Chuong B Do
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  5. Dena G Hernandez
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  6. Mohamad Saad
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  7. Anita L DeStefano
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  8. Eleanna Kara
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  9. Jose Bras
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  10. Manu Sharma
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  11. Claudia Schulte
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  12. Margaux F Keller
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  13. Sampath Arepalli
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  14. Christopher Letson
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  15. Connor Edsall
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  16. Hreinn Stefansson
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  17. Xinmin Liu
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  18. Hannah Pliner
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  19. Joseph H Lee
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  20. Rong Cheng
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  21. M Arfan Ikram
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  22. John P A Ioannidis
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  23. Georgios M Hadjigeorgiou
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  24. Joshua C Bis
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  25. Maria Martinez
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  26. Joel S Perlmutter
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  27. Alison Goate
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  28. Karen Marder
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  29. Brian Fiske
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  30. Margaret Sutherland
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  31. Georgia Xiromerisiou
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  32. Richard H Myers
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  33. Lorraine N Clark
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  34. Kari Stefansson
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  35. John A Hardy
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  36. Peter Heutink
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  37. Honglei Chen
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  38. Nicholas W Wood
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  39. Henry Houlden
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  40. Haydeh Payami
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  41. Alexis Brice
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  42. William K Scott
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  43. Thomas Gasser
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  44. Lars Bertram
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  45. Nicholas Eriksson
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  46. Tatiana Foroud
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  47. Andrew B Singleton
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Consortia

International Parkinson's Disease Genomics Consortium (IPDGC)

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

23andMe

GenePD

NeuroGenetics Research Consortium (NGRC)

Hussman Institute of Human Genomics (HIHG)

The Ashkenazi Jewish Dataset Investigator

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

North American Brain Expression Consortium (NABEC)

United Kingdom Brain Expression Consortium (UKBEC)

Greek Parkinson's Disease Consortium

Alzheimer Genetic Analysis Group

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.

Corresponding author

Correspondence to Andrew B Singleton.

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The authors declare no competing financial interests.

Additional information

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

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

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

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

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

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

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

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

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

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

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

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

Supplementary information

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Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–5. (PDF 22689 kb)

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Nalls, M., Pankratz, N., Lill, C. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 46, 989–993 (2014). https://doi.org/10.1038/ng.3043

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