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

Abstract

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.

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Acknowledgements

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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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.

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Correspondence to Haydeh Payami.

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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). https://doi.org/10.1038/ng.642

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