Please use this identifier to cite or link to this item: https://doi.org/10.1002/mds.28583
Title: Trans-Ethnic Fine-Mapping of the Major Histocompatibility Complex Region Linked to Parkinson's Disease
Authors: Naito, Tatsuhiko
Satake, Wataru
Ogawa, Kotaro
Suzuki, Ken
Hirata, Jun
Foo, Jia Nee
Tan, Eng-King 
Toda, Tatsushi
Okada, Yukinori
Keywords: Parkinson's disease
HLA
MHC
fine-mapping
trans-ethnic analysis
Issue Date: 11-May-2021
Publisher: John Wiley and Sons Inc
Citation: Naito, Tatsuhiko, Satake, Wataru, Ogawa, Kotaro, Suzuki, Ken, Hirata, Jun, Foo, Jia Nee, Tan, Eng-King, Toda, Tatsushi, Okada, Yukinori (2021-05-11). Trans-Ethnic Fine-Mapping of the Major Histocompatibility Complex Region Linked to Parkinson's Disease. Movement Disorders 36 (8) : 1805-1814. ScholarBank@NUS Repository. https://doi.org/10.1002/mds.28583
Rights: Attribution 4.0 International
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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Source Title: Movement Disorders
URI: https://scholarbank.nus.edu.sg/handle/10635/232218
ISSN: 0885-3185
DOI: 10.1002/mds.28583
Rights: Attribution 4.0 International
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