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.
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Software and codes used for this study are available from URLs or upon request to the authors.
HLA data have been deposited at the National Bioscience Database Center (NBDC) Human Database (research ID: hum0114) as open data without any access restrictions. GWAS data and phenotype data of the BBJ individuals are available at the NBDC Human Database (research ID: hum0014).
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We thank T. Aoi for kind support of the study. This research was supported by the Tailor-Made Medical Treatment program (the BioBank Japan Project) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED), MEXT KAKENHI (221S0002), Bioinformatics Initiative of Osaka University Graduate School of Medicine, and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University. Y.O. was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (15H05670, 15H05911 and 15K14429), AMED (18gm6010001h0003 and 18ek0410041h0002), Takeda Science Foundation, the Uehara Memorial Foundation, the Naito Foundation, Daiichi Sankyo Foundation of Life Science, Senri Life Science Foundation and Suzuken Memorial Foundation. K.H. was supported by JSPS KAKENHI grant no. P16H06502 ‘Neo-self’. J.H. is an employee of Teijin Pharma Limited. Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics.
The authors declare no competing interests.
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Hirata, J., Hosomichi, K., Sakaue, S. et al. Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population. Nat Genet 51, 470–480 (2019). https://doi.org/10.1038/s41588-018-0336-0
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