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

Abstract

A BS TRACT: 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.

The Interaction betweenHLA‐DRB1and Smoking in Parkinson's Disease Revisited

“…We also performed analyses restricted to a single peptide (Tyrosine 39, Y39) that induces T cell responses in PD patients 11 and was previously used for binding affinity predictions. 2…”

HLA imputation and its application to genetic and molecular fine-mapping of the MHC region in autoimmune diseases

“…Although it might be challenging to perform a detailed fine-mapping, such as haplotype analysis, reliable conditional analysis, and additional adjustment of covariates, DISH would play a sufficient role in obtaining meaningful inferences. We recently conducted trans-ethnic fine-mapping for Parkinson's disease (PD) by integrating GWAS summary statistics from different studies to detect functionally plausible risk-associated HLA variants [7].…”

“…Not confined to so-called autoimmune diseases, MHC fine-mapping studies have successfully identified the risk HLA variants of different diseases, such as infectious diseases [75,76], malignant tumors [77,78], and neurological diseases [7,79]. These studies could expand our knowledge of the involvement of autoimmunity in the progression of such diseases.…”

“…The altered binding affinity by the causal HLA alleles can be experimentally validated using HLA-peptide binding assay [99,100]. Otherwise, if the epitope of an autoantigen for a disease of interest is already known, in silico prediction tools for HLA binding affinity could also be helpful to obtain a meaningful inference [7,101]. Antigen peptides presented by HLA molecules are recognized by T cell receptors (TCRs), leading to antigen-specific immune responses.…”

“…The MHC is the region with the highest number of disease associations reported in genome-wide association studies (GWAS) [5]. These associations included those "non-autoimmune diseases," such as cardiovascular, metabolic, and neurological diseases, implying immunerelated mechanisms behind the progression of these diseases and the broader significance of the MHC region [6,7]. Among the genes densely present in the MHC region, human leukocyte antigen (HLA) genes are considered to explain most of the genetic heritability of MHC.…”