PMID- 33973677
OWN - NLM
STAT- MEDLINE
DCOM- 20210831
LR  - 20240403
IS  - 1531-8257 (Electronic)
IS  - 0885-3185 (Print)
IS  - 0885-3185 (Linking)
VI  - 36
IP  - 8
DP  - 2021 Aug
TI  - Trans-Ethnic Fine-Mapping of the Major Histocompatibility Complex Region Linked 
      to Parkinson's Disease.
PG  - 1805-1814
LID - 10.1002/mds.28583 [doi]
AB  - 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-DRbeta1 (P = 6.0 x 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 alpha-synuclein epitope than other 
      alleles (P = 9.6 x 10(-4) ). Stepwise conditional analysis suggested additional 
      independent associations at Ala69 in HLA-B (P = 1.0 x 10(-7) ). A subanalysis in 
      Europeans suggested additional independent associations at non-HLA genes in the 
      class III MHC region (EHMT2; P = 2.5 x 10(-7) ). CONCLUSIONS: Our study 
      highlights the shared and distinct genetic features of the MHC region in patients 
      with PD across ethnicities. (c) 2021 The Authors. Movement Disorders published by 
      Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder 
      Society.
CI  - (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on 
      behalf of International Parkinson and Movement Disorder Society.
FAU - Naito, Tatsuhiko
AU  - Naito T
AUID- ORCID: 0000-0002-2779-4600
AD  - Department of Statistical Genetics, Osaka University Graduate School of Medicine, 
      Suita, Japan.
AD  - Department of Neurology, Graduate School of Medicine, The University of Tokyo, 
      Tokyo, Japan.
FAU - Satake, Wataru
AU  - Satake W
AD  - Department of Neurology, Graduate School of Medicine, The University of Tokyo, 
      Tokyo, Japan.
FAU - Ogawa, Kotaro
AU  - Ogawa K
AD  - Department of Statistical Genetics, Osaka University Graduate School of Medicine, 
      Suita, Japan.
AD  - Department of Neurology, Osaka University Graduate School of Medicine, Suita, 
      Japan.
FAU - Suzuki, Ken
AU  - Suzuki K
AUID- ORCID: 0000-0003-1065-3593
AD  - Department of Statistical Genetics, Osaka University Graduate School of Medicine, 
      Suita, Japan.
FAU - Hirata, Jun
AU  - Hirata J
AD  - Department of Statistical Genetics, Osaka University Graduate School of Medicine, 
      Suita, Japan.
AD  - Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Hino, 
      Japan.
FAU - Foo, Jia Nee
AU  - Foo JN
AUID- ORCID: 0000-0001-9899-2308
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 
      Singapore, Singapore.
AD  - Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore.
FAU - Tan, Eng-King
AU  - Tan EK
AD  - Department of Neurology, National Neuroscience Institute, Singapore General 
      Hospital, Singapore, Singapore.
AD  - Duke-National University of Singapore Medical School, Singapore, Singapore.
FAU - Toda, Tatsushi
AU  - Toda T
AD  - Department of Neurology, Graduate School of Medicine, The University of Tokyo, 
      Tokyo, Japan.
FAU - Okada, Yukinori
AU  - Okada Y
AUID- ORCID: 0000-0002-0311-8472
AD  - Department of Statistical Genetics, Osaka University Graduate School of Medicine, 
      Suita, Japan.
AD  - Laboratory of Statistical Immunology, Immunology Frontier Research Center, Osaka 
      University, Suita, Japan.
AD  - Integrated Frontier Research for Medical Science Division, Institute for Open and 
      Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210511
PL  - United States
TA  - Mov Disord
JT  - Movement disorders : official journal of the Movement Disorder Society
JID - 8610688
RN  - 0 (Histocompatibility Antigens)
RN  - EC 2.1.1.43 (EHMT2 protein, human)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
SB  - IM
MH  - Alleles
MH  - Genetic Predisposition to Disease/genetics
MH  - Genome-Wide Association Study
MH  - Haplotypes
MH  - Histocompatibility Antigens
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - Major Histocompatibility Complex
MH  - *Parkinson Disease/genetics
MH  - Polymorphism, Single Nucleotide
PMC - PMC8453830
OTO - NOTNLM
OT  - Parkinson's disease; HLA; MHC; fine-mapping; trans-ethnic analysis
EDAT- 2021/05/12 06:00
MHDA- 2021/09/01 06:00
PMCR- 2021/09/21
CRDT- 2021/05/11 09:34
PHST- 2021/02/25 00:00 [revised]
PHST- 2020/12/21 00:00 [received]
PHST- 2021/03/02 00:00 [accepted]
PHST- 2021/05/12 06:00 [pubmed]
PHST- 2021/09/01 06:00 [medline]
PHST- 2021/05/11 09:34 [entrez]
PHST- 2021/09/21 00:00 [pmc-release]
AID - MDS28583 [pii]
AID - 10.1002/mds.28583 [doi]
PST - ppublish
SO  - Mov Disord. 2021 Aug;36(8):1805-1814. doi: 10.1002/mds.28583. Epub 2021 May 11.