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

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

Research output: Contribution to journalArticlepeer-review

464 Scopus citations

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 SNCA2, 6-8and MAPT3, 7-9, replicated an association with GAK9 (using data from the NGRC and a previous study9, 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-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.

Original languageEnglish (US)
Pages (from-to)781
Number of pages1
JournalNature genetics
Volume42
Issue number9
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • Genetics

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