Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease

Nature Genetics volume 41, pages1303–1307(2009)Cite this article

Abstract

To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 × 10−12) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 × 10−9). We also detected strong associations at SNCA on 4q22 (P = 7.35 × 10−17) and LRRK2 on 12q12 (P = 2.72 × 10−8), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

Access options

Figure 1: Genome-wide association results from the discovery phase.
Figure 2: Regional association plots and linkage disequilibrium structure for the four PD risk loci.

References

  1. 1

    de Rijk, M.C. et al. Prevalence of parkinsonism and Parkinson's disease in Europe: the EUROPARKINSON collaborative study. J. Neurol. Neurosurg. Psychiatry 62, 10–15 (1997).

    CAS  Article  Google Scholar 

  2. 2

    Polymeropoulos, M.H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  Article  Google Scholar 

  3. 3

    Paisán-Ruíz, C. et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595–600 (2004).

    Article  Google Scholar 

  4. 4

    Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Farrer, M.J. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat. Rev. Genet. 7, 306–318 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Thomas, B. & Beal, M.F. Parkinson's disease. Hum. Mol. Genet. 16 Spec No. 2, R183–R194 (2007).

    CAS  Article  Google Scholar 

  7. 7

    Warner, T.T. & Schapira, A.H. Genetic and environmental factors in the cause of Parkinson's disease. Ann. Neurol. 53 (Suppl 3), S16–S23 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Pals, P. et al. α-Synuclein promoter confers susceptibility to Parkinson's disease. Ann. Neurol. 56, 591–595 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Mizuta, I. et al. Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum. Mol. Genet. 15, 1151–1158 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Müller, J.C. et al. Multiple regions of α-synuclein are associated with Parkinson's disease. Ann. Neurol. 57, 535–541 (2005).

    Article  Google Scholar 

  11. 11

    Aharon-Peretz, J., Rosenbaum, H. & Gershoni-Baruch, R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351, 1972–1977 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Maraganore, D.M. et al. High-resolution whole-genome association study of Parkinson disease. Am. J. Hum. Genet. 77, 685–693 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Fung, H.C. et al. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 5, 911–916 (2006).

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

    Welcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  16. 16

    Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Simón-Sánchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. advance online publication, doi:10.1038/ng.487 (15 November 2009).

  18. 18

    Kolisek, M. et al. SLC41A1 is a novel mammalian Mg2+ carrier. J. Biol. Chem. 283, 16235–16247 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Garruto, R.M. et al. Disappearance of high-incidence amyotrophic lateral sclerosis and parkinsonism-dementia on Guam. Neurology 35, 193–198 (1985).

    CAS  Article  Google Scholar 

  20. 20

    Shimizu, F. et al. Cloning and chromosome assignment to 1q32 of a human cDNA (RAB7L1) encoding a small GTP-binding protein, a member of the RAS superfamily. Cytogenet. Cell Genet. 77, 261–263 (1997).

    CAS  Article  Google Scholar 

  21. 21

    Ostvold, A.C. et al. Molecular cloning of a mammalian nuclear phosphoprotein NUCKS, which serves as a substrate for Cdk1 in vivo. Eur. J. Biochem. 268, 2430–2440 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Yamamoto-Katayama, S. et al. Crystallographic studies on human BST-1/CD157 with ADP-ribosyl cyclase and NAD glycohydrolase activities. J. Mol. Biol. 316, 711–723 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Lee, H.C. et al. Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. Annu. Rev. Pharmacol. Toxicol. 41, 317–345 (2001).

    Article  Google Scholar 

  25. 25

    Wilson, C.J. & Callaway, J.C. Coupled oscillator model of the dopaminergic neuron of the substantia nigra. J. Neurophysiol. 83, 3084–3100 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Chan, C.S. et al. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease. Nature 447, 1081–1086 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Surmeier, D.J. Calcium, ageing, and neuronal vulnerability in Parkinson's disease. Lancet Neurol. 6, 933–938 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Singleton, A.B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Uldry, M. et al. Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain. EMBO J. 20, 4467–4477 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Skipper, L. et al. Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson's disease. Hum. Mol. Genet. 14, 3549–3556 (2005).

    CAS  Article  Google Scholar 

  31. 31

    Biskup, S. et al. Common variants of LRRK2 are not associated with sporadic Parkinson's disease. Ann. Neurol. 58, 905–908 (2005).

    CAS  Article  Google Scholar 

  32. 32

    Smith, W.W. et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 9, 1231–1233 (2006).

    CAS  Article  Google Scholar 

  33. 33

    West, A.B. et al. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. USA 102, 16842–16847 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Gilks, W.P. et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415–416 (2005).

    CAS  PubMed  Google Scholar 

  35. 35

    Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).

    CAS  Article  Google Scholar 

  36. 36

    Pittman, A.M. et al. Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J. Med. Genet. 42, 837–846 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Webb, A. et al. Role of the tau gene region chromosome inversion in progressive supranuclear palsy, corticobasal degeneration, and related disorders. Arch. Neurol. 65, 1473–1478 (2008).

    Article  Google Scholar 

  38. 38

    Healy, D.G. et al. Tau gene and Parkinson's disease: a case-control study and meta-analysis. J. Neurol. Neurosurg. Psychiatry 75, 962–965 (2004).

    CAS  Article  Google Scholar 

  39. 39

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  Google Scholar 

  40. 40

    International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  41. 41

    Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    CAS  Article  Google Scholar 

  42. 42

    Barrett, J.C., Fry, B., Maller, J. & Daly, M. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We are grateful to the individuals with PD who participated in this study. We also thank T. Takeshima and E. Ohta for PD samples, H. Inoko and K. Tokunaga for control samples, M. Kanagawa and K. Ura for editing, K. Yasuno and R. Ashida for analyses, and K. Yamada for genotyping. We appreciate all the volunteers and participating institutions of BioBank Japan for samples. This work was supported by a grant from Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST); by the Global COE program and KAKENHI (17019044 and 19590990), both from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by the Grant-in-Aid for 'the Research Committee for the Neurodegenerative Diseases' of the Research on Measures for Intractable Diseases and Research Grant (H19-Genome-Ippan-001), all from the Ministry of Health, Labor and Welfare of Japan.

Author information

Affiliations

  1. Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan

    Wataru Satake, Yuko Nakabayashi, Ikuko Mizuta, Yushi Hirota, Chiyomi Ito & Tatsushi Toda

  2. Division of Clinical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

    Wataru Satake, Yuko Nakabayashi, Ikuko Mizuta, Yushi Hirota, Chiyomi Ito & Tatsushi Toda

  3. Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan

    Wataru Satake & Saburo Sakoda

  4. Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Michiaki Kubo, Takahisa Kawaguchi, Tatsuhiko Tsunoda & Yusuke Nakamura

  5. Department of Neurology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

    Masahiko Watanabe

  6. Division of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Atsushi Takeda

  7. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

    Hiroyuki Tomiyama & Nobutaka Hattori

  8. Department of Neurology, Tottori University Faculty of Medicine, Yonago, Japan

    Kenji Nakashima

  9. Department of Neurology, Sagamihara National Hospital, Sagamihara, Japan

    Kazuko Hasegawa

  10. Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan

    Fumiya Obata

  11. RIKEN Brain Science Institute, Saitama, Japan

    Takeo Yoshikawa

  12. Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Hideshi Kawakami

  13. Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu, Japan

    Mitsutoshi Yamamoto

  14. Department of Neurology, National Center Hospital of Neurology and Psychiatry, Kodaira, Japan

    Miho Murata

  15. Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yusuke Nakamura

Authors
  1. Wataru Satake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuko Nakabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ikuko Mizuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yushi Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chiyomi Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michiaki Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takahisa Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tatsuhiko Tsunoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masahiko Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Atsushi Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroyuki Tomiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kenji Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kazuko Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fumiya Obata
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Takeo Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hideshi Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Saburo Sakoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Mitsutoshi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Nobutaka Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Miho Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Yusuke Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Tatsushi Toda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T. Toda conceived the study. W.S., I.M. and T. Toda designed the study. W.S., Y.N., C.I., M.K. and T.Y. performed genotyping. W.S. and T. Toda wrote the manuscript. W.S., T.K. and T. Tsunoda performed data analysis. W.S., I.M., Y.H., M.W., A.T., H.T., K.N., K.H., F.O., H.K., S.S., M.Y., N.H., M.M. and T. Toda managed Parkinson clinical information and DNA samples. M.K. and Y.N. managed DNA samples belonging to BioBank Japan. T. Toda obtained funding for the study.

Corresponding author

Correspondence to Tatsushi Toda.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1–4. (PDF 576 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Satake, W., Nakabayashi, Y., Mizuta, I. 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). https://doi.org/10.1038/ng.485

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing