Association between Parkinson's disease and the HLA‐DRB1 locus

Two genome‐wide association studies (GWASs) recently highlighted the HLA‐DRA and HLA‐DRB5 genes as associated with Parkinson disease (PD). However, because HLA‐DRA displays a low level of polymorphisms and HLA‐DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA‐DR region; (2) to identify PD‐associated HLA alleles; and (3) to perform a meta‐analysis of our top finding. As part of 2 French population‐based case–control studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single‐nucleotide polymorphisms (SNPs) in the HLA‐DR region. HLA‐DRB1 alleles were imputed using the HLA*IMP software. HLA typing was performed in a subsample of the participants. We performed a meta‐analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.57–0.87) within the HLA‐DRB1 gene, which encodes the most polymorphic HLA‐DR chain (DRβ). A meta‐analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.82–0.91; P < .0001). SNP‐based imputation of HLA alleles showed an inverse association between PD and the HLA‐DRB1*04 allele. We replicated an association between PD and the HLA‐DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA‐DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology. © 2012 Movement Disorder Society