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

Abstract

Objective: Previous studies suggested a role for the immune system in Parkinson disease (PD), and one of the hits in recent genome-wide association studies (GWASs) of PD is within the human leukocyte antigen (HLA) locus. Several associations of different HLA genes have been suggested, yet it is not clear which associations are relevant for PD. 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 analyses 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 analyses followed by amino-acid analysis and conditional analyses 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<8.23x10-9 for all three variants). No other effects were present after adjustment for these amino acids. Interpretation: 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.

Establishing gene regulatory networks from Parkinson’s disease risk loci

“…We identified a spatial eQTL between rs504594 and HLA-DRB1 in both the foetal cortex and adult brain (including cortex and SN), implicating this regulatory eQTLgene connection in both the neurodevelopment and neurodegenerative stages of PD. Interestingly, rs504594 (previous ID: rs112485776) was recently validated in a SNP-level meta-analysis (OR = 0.87), with results displaying no residual HLA effect in adults after adjusting for the SNP 75 . Instead, three amino acid polymorphisms within the HLA-DRB1 gene were identified as drivers of the association between the HLA region and PD risk 75 .…”

“…Interestingly, rs504594 (previous ID: rs112485776) was recently validated in a SNP-level meta-analysis (OR = 0.87), with results displaying no residual HLA effect in adults after adjusting for the SNP 75 . Instead, three amino acid polymorphisms within the HLA-DRB1 gene were identified as drivers of the association between the HLA region and PD risk 75 . We agree that the impacts of rs504594 are contingent upon the HLA-DRB1 allele -both in terms of regulation and protein sequence.…”

Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated Tau PHF6 sequences

“…The PD samples included in the analysis are part of the following datasets for which the phenotyping, genotyping and quality control has been described elsewhere 10,18,19,26,29,66 The samples assessed for AD and Lewy-body neuropathology included genetic data from the Rush Religious Orders Study and Memory and Aging Project (ROSMAP) 67 and from the Alzheimer"s Disease Center (ADC) cohorts 1 to 7 parts of the ADGC 68 , and Extended Data Figure 6. HLA binding predictions for PHF6.…”

“…Two recent large studies in PD 18,19 have shown that the HLA signal in PD is best summarized by a primary protective effect of HLA-DRB1 amino acids 13H and 33H shared by all HLA-DRB1*04 subtypes. HLA-DRB1 amino acids 11V also showed a strong association; this amino acid is shared by HLA-DRB1*04 and HLA-DRB1*10:01, a subtype not associated with the disease.…”

“…Twofield resolution alleles of HLA-A, HLA-B, HLA-C class I genes, and HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1 class II genes were imputed using R package HIBAG v1.22 24 for the following dataset: EADB, GR@ACE, GERAD, EADI, DemGene, Bonn, CCHS, UK Biobank, IPDGC, NINDS, NGRC, McGill, Oslo, PPMI, APDGC, LARGE-PD, ADSP, ADGC, GARD, NCGG. When available, training sets specific to ancestry (European, East Asian, Latino, African) and genotyping array were used, either available through HIBAG 24 or trained in-house as previously described 19 .…”