Fine mapping of the HLA locus in Parkinson’s disease in Europeans

Objective To fine map the association between human leukocyte antigen ( HLA) genes and Parkinson’s disease (PD) that was discovered using genome-wide association studies (GWASs). Methods We performed a thorough analysis of the HLA locus in 13,770 PD patients, 20,214 proxy-cases and 490,861 controls of European origin. We used GWAS data to impute HLA types and performed multiple regression models to examine the association of specific HLA types, different haplotypes and specific amino acid changes. We further performed conditional analyzes to identify specific alleles or genetic variants that drive the association with PD. Results Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1 *03:01, HLA-DQB1 *03:02, HLA-DRB1 *04:01 and HLA-DRB1 *04:04. Haplotype analyzes followed by amino-acid analysis and conditional analyzes suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1 *04 subtypes - 11V, 13H and 33H (OR=0.87 95%CI=0.83-0.90, p <8.23×10 −9 for all three variants). No other effects were present after adjustment for these amino acids. Conclusions Our results suggest that specific variants in the HLA-DRB1 gene are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to identification of new targets for therapeutics development.