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

Journal name:
Nature Genetics
Volume:
42,
Pages:
781–785
Year published:
DOI:
doi:10.1038/ng.642
Received
Accepted
Published online

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.

At a glance

Figures

  1. Genome-wide association P values.
    Figure 1: Genome-wide association P values.

    The Manhattan plot shows the P values for association of 811,597 SNPs with Parkinson's disease. SNPs that surpassed genome-wide significance (P < 5 × 10−8) were on chromosomes 4 (SNCA region) and 6 (HLA-DRA). SNCA was known to be associated with Parkinson's disease; however, the association with HLA was not previously known. The other known Parkinson's disease–associated region is on chromosome 17 (MAPT region), which replicated at P = 1.3 × 10−6.

  2. Signals of association with Parkinson's disease in the HLA region.
    Figure 2: Signals of association with Parkinson's disease in the HLA region.

    Shown is a 1-Mb region centered on the association peak, located at rs3129882 in intron 1 of HLA-DRA, spanning from base pair position 32,017,508 to position 33,017,508. The top panel shows all SNPs in this region plotted according to the significance of their association with Parkinson's disease and color coded according to their linkage disequilibrium (r2) with the most significant SNP, rs3129882. Note that rs3129882 is not strongly correlated (defined as r2 ≥ 0.8) with any other HLA variant. The LocusZoom software used here calculates r2 using the HapMap European CEU data. SNPs shown in gray were on the Illumina OMNI chip but not in HapMap, and thus r2 was not calculated with this method. However, using the Haploview software and the NGRC data to estimate r2, none of the variants was strongly correlated with rs3129882 (with all r2 < 0.6; Supplementary Fig. 6). The bottom panel shows the genes in the region, including the closely linked polymorphic HLA-DRB and DQB loci, as well as DRA, DRB5 and DRQA2, whose expression is correlated with variation at rs3129882.

References

  1. Payami, H., Larsen, K., Bernard, S. & Nutt, J. Increased risk of Parkinson′s disease in parents and siblings of patients. Ann. Neurol. 36, 659661 (1994).
  2. Kay, D.M. et al. Genetic association between alpha-synuclein and idiopathic Parkinson's disease. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 147B, 12221230 (2008).
  3. Zabetian, C.P. et al. Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson′s disease. Ann. Neurol. 62, 137144 (2007).
  4. Powers, K.M. et al. Combined effects of smoking, coffee and NSAIDs on Parkinson′s disease risk. Mov. Disord. 23, 8895 (2008).
  5. McCulloch, C.C. et al. Exploring gene-environment interactions in Parkinson′s disease. Hum. Genet. 123, 257265 (2008).
  6. Maraganore, D.M. et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. J. Am. Med. Assoc. 296, 661670 (2006).
  7. Simón-Sánchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 13081312 (2009).
  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, 97109 (2010).
  9. Pankratz, N. et al. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum. Genet. 124, 593605 (2009).
  10. Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 12171224 (2007).
  11. Montgomery, S.B. et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773777 (2010).
  12. McGeer, P.L. & McGeer, E.G. Glial reactions in Parkinson′s disease. Mov. Disord. 23, 474483 (2008).
  13. Chen, H. et al. Nonsteroidal anti-inflammatory drug use and the risk for Parkinson′s disease. Ann. Neurol. 58, 963967 (2005).
  14. Ward, C.D. et al. Parkinson's disease in 65 pairs of twins and in a set of quadruplets. Neurology 33, 815824 (1983).
  15. Tanner, C.M. et al. Parkinson disease in twins: an etiologic study. J. Am. Med. Assoc. 281, 341346 (1999).
  16. Thacker, E.L. & Ascherio, A. Familial aggregation of Parkinson′s disease: a meta-analysis. Mov. Disord. 23, 11741183 (2008).
  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, 276284 (2002).
  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, 13031307 (2009).
  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, 911916 (2006).
  21. Maraganore, D.M. et al. High-resolution whole-genome association study of Parkinson disease. Am. J. Hum. Genet. 77, 685693 (2005).
  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, 241243 (2010).
  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, 745752 (1988).
  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, 861870 (2002).
  25. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559575 (2007).
  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, 519523 (2006).
  27. Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155166 (2001).
  28. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904909 (2006).
  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, 12851291 (1988).
  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, 26652674 (2005).
  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, 160166 (1994).
  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, 599604 (2003).
  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, 598605 (1999).
  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, 22612271 (2010).
  35. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263265 (2005).

Download references

Author information

Affiliations

  1. New York State Department of Health Wadsworth Center, Albany, New York, USA.

    • Taye H Hamza,
    • Alain Laederach,
    • Jennifer Montimurro,
    • Dora Yearout,
    • Denise M Kay,
    • Victoria I Kusel,
    • Randall Collura &
    • Haydeh Payami
  2. Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.

    • Cyrus P Zabetian,
    • Dora Yearout &
    • Ali Samii
  3. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • Cyrus P Zabetian,
    • Dora Yearout &
    • Ali Samii
  4. Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK.

    • Albert Tenesa
  5. Center for Inherited Disease Research (CIDR), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Kimberly F Doheny &
    • Elizabeth Pugh
  6. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.

    • Justin Paschall
  7. Virginia Mason Medical Center, Seattle, Washington, USA.

    • John Roberts
  8. Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, Washington, USA.

    • Alida Griffith
  9. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.

    • William K Scott
  10. Department of Neurology, Oregon Health and Sciences University, Portland, Oregon, USA.

    • John Nutt
  11. Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Stewart A Factor

Contributions

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.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary Text and Figures (536)

    Supplementary Tables 1–5 and Supplementary Figures 1–6

Additional data