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)1-5. 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. © 2010 Nature America, Inc. All rights reserved.