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). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, 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. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.

Figure 1. Genome-wide association P-values

The Manhattan plot shows the P-values for association of 811,597 SNPs with PD. SNPs that surpass genome-wide significance (P<5×10⁻⁸) were on chromosomes 4 (SNCA region) and 6 (HLA-DRA). SNCA was known to be associed with PD, the HLA association is novel. The other known PD-associated region is on chromosme 17 (MAPT region) which replicated at P=1.3×10⁻⁶.

Figure 2. Signals of PD-association within HLA

A one megabase (MB) region was defined centered on the association peak, rs3129882 in intron 1 of HLA-DRA, spanning from base pair (BP) position 32,017,508 to 33,017,508. The top panel shows all SNPs in this region plotted according to the significance of their association with PD and color-coded according to their linkage disequilibrium (r²) with the most significant SNP, rs3129882. Note that rs3129882 is not strongly correlated (defined as r²≥ 0.8)with any other HLA variant. The LocusZoom software used here calculates r² using the HapMap CEU data. SNPs shown in grey were on the Illumina OMNI chip but not on HAPMAP thus r² was not calculated with this method; however, using the Haploview software and the NGRC data to estimate r², none of the variants was strongly correlated with rs3129882 (r²<0.6, Supplementary Fig. 6). The bottom panel shows the genes in the region, including the closely linked polymorphic HLA-DRB and DQB loci, and DRA, DRB5, and DRQA2 whose expression is correlated with the variation at rs3129882.