Abstract
To fine map association signals of human leukocyte antigen (HLA) variants in the major histocompatibility complex (MHC) region, we constructed a Japanese population-specific reference panel (n = 908). We conducted trans-ancestry comparisons of linkage disequilibrium (LD) and haplotype structure for HLA variants using an entropy-based LD measurement, ɛ, and a visualization tool to capture high-dimensional variables. Our Japanese reference panel exhibited stronger LD between HLA genes than European or other East Asian populations, characterized by one population-specific common long-range HLA haplotype. We applied HLA imputation to genome-wide association study (GWAS) data for Graves' disease in Japanese (n = 9,003) and found that amino acid polymorphisms of multiple class I and class II HLA genes independently contribute to disease risk (HLA-DPB1, HLA-A, HLA-B and HLA-DRB1; P < 2.3 × 10−6), with the strongest impact at HLA-DPB1 (P = 1.6 × 10−42). Our study illustrates the value of population-specific HLA reference panels.
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Acknowledgements
We thank N. Kumasaka who originally developed the Disentangler software. We acknowledge T. Aoi and C. Inai for technical assistance and the members of BioBank Japan and the Rotary Club of Osaka-Midosuji District 2660 Rotary International for supporting our study. Y.O. was supported by the Japan Science and Technology Agency (JST), the Japan Society of the Promotion of Science (JSPS), the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Takeda Science Foundation, the Gout Research Foundation, the Tokyo Biochemical Research Foundation and the Japan Rheumatism Foundation. The BioBank Japan Project was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government.
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Y.O. wrote the manuscript. Y.O., Y.K., M. Kanai and A.T. conducted the data analyses. Y.M., K.A. and M. Kubo conducted SNP and HLA genotyping. K.M. and M. Kubo collected the samples. Y.O. and M. Kubo designed the study.
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Supplementary information
Supplementary Text and Figures
Supplementary Tables 1–3. (PDF 309 kb)
Supplementary Table 4
Detailed association results of the HLA variants in the MHC region on Graves' disease risk. (XLSX 1381 kb)
Supplementary Table 5
Stepwise conditional association results of the HLA amino acid positions on Graves' disease risk. (XLSX 17 kb)
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Okada, Y., Momozawa, Y., Ashikawa, K. et al. Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese. Nat Genet 47, 798–802 (2015). https://doi.org/10.1038/ng.3310
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DOI: https://doi.org/10.1038/ng.3310
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