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

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.