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

• Published in: Nature genetics Vol. 51; no. 3; pp. 470 - 480
• Main Authors: Hirata, Jun, Hosomichi, Kazuyoshi, Sakaue, Saori, Kanai, Masahiro, Nakaoka, Hirofumi, Ishigaki, Kazuyoshi, Suzuki, Ken, Akiyama, Masato, Kishikawa, Toshihiro, Ogawa, Kotaro, Masuda, Tatsuo, Yamamoto, Kenichi, Hirata, Makoto, Matsuda, Koichi, Momozawa, Yukihide, Inoue, Ituro, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2019; Nature Publishing Group
• Subjects: 42/47; 45/43; 631/208/205/2138; 631/208/248; 639/705/1042; 692/308/2056; Agriculture; Alleles; Animal Genetics and Genomics; Antigens; Arthritis; Asians - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line; Correlation analysis; Disease; DNA sequencing; Gene Function; Gene mapping; Gene sequencing; Genes; Genetic analysis; Genetic Association Studies - methods; Genetic research; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics; Genotype; Genotype & phenotype; Genotypes; Haplotypes; Heritability; Histocompatibility; Histocompatibility antigen HLA; HLA antigens; Human Genetics; Humans; Leukocytes; Linkage Disequilibrium - genetics; Major Histocompatibility Complex - genetics; Mapping; Medical schools; Methods; Network analysis; Next-generation sequencing; Phenotype; Phenotypes; Polymorphism, Single Nucleotide - genetics; Population; Studies; Tissue typing; Japan
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-018-0336-0

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 (
n
 = 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.
Sequencing of the MHC region in the Japanese population provides insight into population-specific allelic and structural variability. These data enable discovery and fine-mapping of genotype–phenotype associations across 52 phenotypes.