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Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease


Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC)1,2,3,4,5. We confirmed associations with SNCA2,6,7,8 and MAPT3,7,8,9, replicated an association with GAK9 (using data from the NGRC and a previous study9, P = 3.2 × 10−9) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 × 10−8), which replicated in two datasets (meta-analysis P = 1.9 × 10−10). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 × 10−10) and late-onset (P = 2.4 × 10−8) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ10,11. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia12, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk4,13. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.

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Figure 1: Genome-wide association P values.
Figure 2: Signals of association with Parkinson's disease in the HLA region.


  1. Payami, H., Larsen, K., Bernard, S. & Nutt, J. Increased risk of Parkinson′s disease in parents and siblings of patients. Ann. Neurol. 36, 659–661 (1994).

    Article  CAS  Google Scholar 

  2. Kay, D.M. et al. Genetic association between alpha-synuclein and idiopathic Parkinson's disease. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 147B, 1222–1230 (2008).

    Article  Google Scholar 

  3. Zabetian, C.P. et al. Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson′s disease. Ann. Neurol. 62, 137–144 (2007).

    Article  CAS  Google Scholar 

  4. Powers, K.M. et al. Combined effects of smoking, coffee and NSAIDs on Parkinson′s disease risk. Mov. Disord. 23, 88–95 (2008).

    Article  Google Scholar 

  5. McCulloch, C.C. et al. Exploring gene-environment interactions in Parkinson′s disease. Hum. Genet. 123, 257–265 (2008).

    Article  CAS  Google Scholar 

  6. Maraganore, D.M. et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. J. Am. Med. Assoc. 296, 661–670 (2006).

    Article  CAS  Google Scholar 

  7. Simón-Sánchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308–1312 (2009).

    Article  Google Scholar 

  8. 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 

  9. 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 

  10. Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

    Article  CAS  Google Scholar 

  11. Montgomery, S.B. et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010).

    Article  CAS  Google Scholar 

  12. McGeer, P.L. & McGeer, E.G. Glial reactions in Parkinson′s disease. Mov. Disord. 23, 474–483 (2008).

    Article  Google Scholar 

  13. Chen, H. et al. Nonsteroidal anti-inflammatory drug use and the risk for Parkinson′s disease. Ann. Neurol. 58, 963–967 (2005).

    Article  CAS  Google Scholar 

  14. Ward, C.D. et al. Parkinson's disease in 65 pairs of twins and in a set of quadruplets. Neurology 33, 815–824 (1983).

    Article  CAS  Google Scholar 

  15. Tanner, C.M. et al. Parkinson disease in twins: an etiologic study. J. Am. Med. Assoc. 281, 341–346 (1999).

    Article  CAS  Google Scholar 

  16. Thacker, E.L. & Ascherio, A. Familial aggregation of Parkinson′s disease: a meta-analysis. Mov. Disord. 23, 1174–1183 (2008).

    Article  Google Scholar 

  17. Mata, I.F. et al. A SNCA variant associated with Parkinson's disease and plasma α-synuclein level. Arch. Neurol. (in the press).

  18. Hernán, M.A., Takkouche, B., Caamano-Isorna, F. & Gestal-Otero, J.J. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann. Neurol. 52, 276–284 (2002).

    Article  Google Scholar 

  19. 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 

  20. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Hamza, T.H. & Payami, H. The heritability of risk and age at onset of Parkinson′s disease after accounting for known genetic risk factors. J. Hum. Genet. 55, 241–243 (2010).

    Article  CAS  Google Scholar 

  23. Gibb, W.R. & Lees, A. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 51, 745–752 (1988).

    Article  CAS  Google Scholar 

  24. Hughes, A.J., Daniel, S.E., Ben-Shlomo, Y. & Lees, A.J. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125, 861–870 (2002).

    Article  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. Kay, D.M. et al. Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics. Mov. Disord. 21, 519–523 (2006).

    Article  Google Scholar 

  27. Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).

    Article  CAS  Google Scholar 

  28. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  29. McGeer, P.L., Itagaki, S., Boyes, B.E. & McGeer, E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285–1291 (1988).

    Article  CAS  Google Scholar 

  30. Orr, C.F., Rowe, D.B., Mizuno, Y., Mori, H. & Halliday, G.M. A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain 128, 2665–2674 (2005).

    Article  Google Scholar 

  31. Fiszer, U., Mix, E., Fredrikson, S., Kostulas, V. & Link, H. Parkinson's disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol. Scand. 90, 160–166 (1994).

    Article  CAS  Google Scholar 

  32. McGeer, P.L., Schwab, C., Parent, A. & Doudet, D. Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann. Neurol. 54, 599–604 (2003).

    Article  CAS  Google Scholar 

  33. Langston, J.W. et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann. Neurol. 46, 598–605 (1999).

    Article  CAS  Google Scholar 

  34. Reynolds, A.D. et al. Regulatory T cells attenuate th17 cell-mediated nigrastriatal dopaminergic neurodegeneration in a model of Parkinson' disease. J. Immunol. 184, 2261–2271 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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We would like to acknowledge the individuals with Parkinson's disease, their families and the healthy volunteers who participated in this study. We thank T.L. Edwards, J.M. Vance, E.R. Martin, J.L. Haines and M.A. Pericak-Vance for sharing their GWAS data with us; R.H. Myers, J.F. Gusella, T. Foroud and N. Pankratz for making their data public via dbGaP; and J. Degner for assistance with the eQTL data repository website at University of Chicago. We acknowledge M. Adams, M. Zilka and the staff of CIDR for excellent genotyping service, M. Palumbo, C.S. Carmack and the staff of the Computational Biology and Statistics Core of Wadsworth Center for computing support and C. Lambert and G.L. Peterson for developing the randomized plate layout. This project was supported by Award Number R01NS36960 from the National Institute of Neurological Disorders and Stroke. Additional support was provided by an Edmond J. Safra Global Genetic Consortium Grant from the Michael J. Fox Foundation for Parkinson's Disease Research, Merit Review Award from the Department of Veterans Affairs (1I01BX000531), National Institutes of Aging (P30AG08017), National Institute of Mental Health (R21MH087336), Office of Research and Development, Clinical Sciences Research and Development Service, Department of Veteran Affairs, The Intramural Research Program of the US National Institutes of Health (NIH) at the National Library of Medicine and the Close to the Cure Foundation. Genotyping services were provided by CIDR, which is fully funded through a federal contract from the NIH to Johns Hopkins University, contract number HHSN268200782096C. The work described in ref. 8, whose data were used for replication, was funded by NIH grants AG027944 and NS039764. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

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Authors and Affiliations



H.P. established and directs the NGRC in collaboration with C.P.Z., S.A.F. and J.N. The GWAS was designed by and funded through H.P. Subjects were ascertained, diagnosed and characterized by NGRC investigators A.G., J.R., A.S., S.A.F., J.N. and C.P.Z. DNA and phenotype preparations, database operations and final subject selection for the GWAS was carried out by J.M., D.Y., D.M.K. and V.I.K. under the supervision of H.P. and C.P.Z. K.F.D. was in charge of GWAS genotyping and genotyping quality control. T.H.H. performed all statistical analyses with critical feedback from A.T., J.P., E.P. and H.P. V.I.K. and R.C. contributed to bioinformatics and graphic presentations. W.K.S. provided an independent GWAS dataset for replication. A.L. uncovered the regulatory function of rs3129882 using bioinformatics. H.P., T.H.H. and A.T. wrote the paper. All authors participated in reviewing results and assisting with manuscript preparation.

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Correspondence to Haydeh Payami.

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The authors declare no competing financial interests.

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

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