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

Abstract

Parkinson disease (PD) is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study (GWAS) with 2000 PD and 1986 control Caucasian subjects from NeuroGenetics Research Consortium. 1– 5 We confirmed SNCA 2, 6– 8 and MAPT 3, 7– 9; replicated GAK 9 (P _{Pankratz+NGRC}=3.2×10 ⁻⁹); and detected a novel association with HLA (P _NGRC=2.9×10 ⁻⁸) which replicated in two datasets (P _{Meta-analysis}=1.9×10 ⁻¹⁰). We designate the new PD genes PARK17 (GAK) and PARK18 (HLA). PD- HLA association was uniform across genetic and environmental risk strata, and strong in sporadic (P=5.5×10 ⁻¹⁰) and late-onset (P=2.4×10 ⁻⁸) PD. The association peak was at rs3129882, a non-coding variant in HLA-DRA. Two studies suggested rs3129882 influences expression of HLA- DR and HLA-DQ. 10, 11 PD brains exhibit up-regulation of DR antigens and presence of DR-positive reactive microglia. 12 Moreover, non-steroidal anti-inflammatory drugs (NSAID) reduce PD risk. 4, 13 The genetic association with HLA coalesces the evidence for involvement of the immune system and offers new targets for drug development and pharmacogenetics.