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

Research output: Contribution to journalArticle

  • Taye H. Hamza
  • Cyrus P. Zabetian
  • Albert Tenesa
  • Alain Laederach
  • Jennifer Montimurro
  • Dora Yearout
  • Denise M. Kay
  • Kimberly F. Doheny
  • Justin Paschall
  • Elizabeth Pugh
  • Victoria I. Kusel
  • Randall Collura
  • John Roberts
  • Alida Griffith
  • Ali Samii
  • William K. Scott
  • John Nutt
  • Stewart A. Factor
  • Haydeh Payami

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    Rights statement: Published in final edited form as: Nat Genet. 2010 September ; 42(9): 781–785. doi:10.1038/ng.642.

    Accepted author manuscript, 741 KB, PDF-document

http://www.nature.com/ng/journal/v42/n9/full/ng.642.html
Original languageEnglish
Pages (from-to)781-785
Number of pages6
JournalNature Genetics
Volume42
Issue number9
DOIs
StatePublished - Sep 2010

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)(1-5). We confirmed associations with SNCA(2,6-8) and MAPT(3,7-9), replicated an association with GAK9 (using data from the NGRC and a previous study(9), P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 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-DQ(10,11). The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia(12), and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk(4,13). The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.

    Research areas

  • Adult, Age of Onset, Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Linkage, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, HLA Antigens, Humans, Male, Meta-Analysis as Topic, Middle Aged, Odds Ratio, Parkinson Disease, Young Adult

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