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      Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese.

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          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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          Author and article information

          Journal
          Nat. Genet.
          Nature genetics
          1546-1718
          1061-4036
          Jul 2015
          : 47
          : 7
          Affiliations
          [1 ] 1] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. [2] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
          [2 ] Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
          [3 ] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
          [4 ] Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
          [5 ] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
          Article
          ng.3310
          10.1038/ng.3310
          26029868
          12e0939c-6d0b-4665-92fd-5e5561b15c87
          History

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