Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Toyo, Japan.
Pharmacogenomics J. 2020 Oct;20(5):695-704. doi: 10.1038/s41397-020-0156-3. Epub 2020 Feb 11.
An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB103:01, DRB104:05, DQA103:03, and DQB104:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.
一种人类白细胞抗原 (HLA) 推测算法有助于探索新的疾病关联。然而,实现高推测准确性的关键是使用特定于人群的 HLA 推测参考。在这项研究中,使用了台湾生物银行 (TWB) 中的 1012 名个体的子集,这些个体同时进行了全基因组 SNP 芯片和基于 NGS 的 HLA 分型,以建立台湾 HLA 推测参考。使用 HIBAG 包以两位和三位字段分辨率生成八个 HLA 基因座的推测参考。通过内部验证来评估每个 HLA 基因的调用阈值和准确性。通过推测的 HLA 等位基因来验证与类风湿关节炎 (RA) 相关的 HLA 类 II 基因。我们的台湾人群特异性参考在两位字段的 HLA 推测准确性平均为 98.11%,在三位字段分辨率的 HLA 推测准确性平均为 98.08%。在 23972 名 TWB 受试者中,推测 HLA 等位基因的频率分布与在一般台湾人群中报道的基于 PCR 的 HLA 等位基因在总体上具有可比性,这些等位基因来自于等位基因频率网数据库。我们复制了四个常见的 HLA 等位基因(HLA-DRB103:01、DRB104:05、DQA103:03 和 DQB104:01),它们与 RA 显著相关。这些人群特异性参考为在大规模基于人群的研究中研究 HLA 变异与人类疾病的关联提供了一个有用的工具。