Trans-Ethnic Fine-Mapping of the Major Histocompatibility Complex Region Linked to Parkinson's Disease

Abstract

Background: Despite evidence for the role of human leukocyte antigen (HLA) in the genetic predisposition to Parkinson's disease (PD), the complex haplotype structure and highly polymorphic feature of the major histocompatibility complex (MHC) region has hampered a unified insight on the genetic risk of PD. In addition, a majority of the reports focused on Europeans, lacking evidence on other populations.

Objectives: The aim of this study is to elucidate the genetic features of the MHC region associated with PD risk in trans-ethnic cohorts.

Methods: We conducted trans-ethnic fine-mapping of the MHC region for European populations (14,650 cases and 1,288,625 controls) and East Asian populations (7712 cases and 27,372 controls). We adopted a hybrid fine-mapping approach including both HLA genotype imputation of genome-wide association study (GWAS) data and direct imputation of HLA variant risk from the GWAS summary statistics.

Results: Through trans-ethnic MHC fine-mapping, we identified the strongest associations at amino acid position 13 of HLA-DRβ1 (P = 6.0 × 10^-15 ), which explains the majority of the risk in HLA-DRB1. In silico prediction revealed that HLA-DRB1 alleles with histidine at amino acid position 13 (His13) had significantly weaker binding affinity to an α-synuclein epitope than other alleles (P = 9.6 × 10^-4 ). Stepwise conditional analysis suggested additional independent associations at Ala69 in HLA-B (P = 1.0 × 10^-7 ). A subanalysis in Europeans suggested additional independent associations at non-HLA genes in the class III MHC region (EHMT2; P = 2.5 × 10^-7 ).

Conclusions: Our study highlights the shared and distinct genetic features of the MHC region in patients with PD across ethnicities. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; HLA; MHC; fine-mapping; trans-ethnic analysis.

FIG. 1

The participants and workflow of our study. We conducted the trans‐ethnic human leukocyte antigen (HLA) fine‐mapping of the Parkinson's disease (PD) risk. Our study included in total seven PD genome‐wide association studies (GWAS) from European and east Asian populations (22,362 PD cases and 1,315,997 controls). UKB, UK Biobank. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Regional association plots of the human leukocyte antigen (HLA) variants with Parkinson's disease. Diamonds represent −log₁₀ (P values) for the tested HLA variants, including single‐nucleotide variants (SNVs), classical alleles, and amino acid (AA) polymorphisms of the HLA genes. The dashed black horizontal lines represent the study‐wide significance threshold of P = 3.3 × 10⁻⁶. The physical positions of the HLA genes on chromosome 6 are shown at the bottom. Each panel shows the association plot in the process of stepwise conditional regression analysis in the trans‐ethnic meta‐analysis: (a) nominal results, (b) results conditioned on HLA‐DRβ1 AA position 13, and (c) results conditioned on HLA‐DRβ1 AA position 13 and HLA‐B AA position 69. Each panel shows the association plot in the meta‐analysis in the European populations: (d) nominal results and (e) results conditioned on HLA‐DRβ1 AA position 13 and HLA‐B AA position 69. (f) The association plot in the meta‐analysis in the East Asian populations. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

Risk‐associated amino acid polymorphisms and in silico predicted binding affinity of HLA‐DRB1 alleles to an α‐synuclein epitope. (a) The results of in silico predicted binding affinity of HLA‐DRB1 alleles to the Y39 epitope of α‐synuclein are shown in boxplots and compared between alleles with and without His (left) and Arg (right) in position 13 of HLA‐DRβ1. His13 in HLA‐DRβ1 is almost consistent with HLA‐DRB1*04, and HLA‐DRB1*15:01 has Arg13 in HLA‐DRβ1. (b) Three‐dimensional ribbon models of the human leukocyte antigen (HLA) proteins associated with Parkinson's disease (PD) risk. The protein structures of HLA‐B and HLA‐DR are based on Protein Data Bank entries 2BVP and 3PDO, respectively, which were displayed using UCSF Chimera version 1.14. Residues at the PD risk‐associated amino acid positions are colored red (arrows). Arg, arginine; His, histidine. [Color figure can be viewed at wileyonlinelibrary.com]