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Nat Genet. 2019 Jan 28. doi: 10.1038/s41588-018-0336-0. [Epub ahead of print]

Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population.

Author information

1
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
2
Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Hino, Japan.
3
Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Ishikawa, Japan.
4
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
5
Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
6
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
7
Division of Human Genetics, National Institute of Genetics, Shizuoka, Japan.
8
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
9
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan.
10
Department of Otorhinolaryngology, Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
11
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
12
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
13
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
14
Laboratory of Genome Technology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
15
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
16
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
17
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
18
Kyoto-McGill International Collaborative School in Genomic Medicine, Sakyo-ku, Kyoto, Japan.
19
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan. yokada@sg.med.osaka-u.ac.jp.
20
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. yokada@sg.med.osaka-u.ac.jp.
21
Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan. yokada@sg.med.osaka-u.ac.jp.

Abstract

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (nā€‰=ā€‰1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype-phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes.

PMID:
30692682
DOI:
10.1038/s41588-018-0336-0

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