Ritari Jarmo, Hyvärinen Kati, Clancy Jonna, Partanen Jukka, Koskela Satu
Research and Development, Finnish Red Cross Blood Service, Kivihaantie 7, 00310 Helsinki, Finland.
NAR Genom Bioinform. 2020 May 6;2(2):lqaa030. doi: 10.1093/nargab/lqaa030. eCollection 2020 Jun.
The HLA genes, the most polymorphic genes in the human genome, constitute the strongest single genetic susceptibility factor for autoimmune diseases, transplantation alloimmunity and infections. HLA imputation via statistical inference of alleles based on single-nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) with alleles is a powerful first-step screening tool. Due to different LD structures between populations, the accuracy of HLA imputation may benefit from matching the imputation reference with the study population. To evaluate the potential advantage of using population-specific reference in HLA imputation, we constructed an HLA reference panel consisting of 1150 Finns with 5365 major histocompatibility complex region SNPs consistent between genome builds. We evaluated the accuracy of the panel against a European panel in an independent test set of 213 Finnish subjects. We show that the Finnish panel yields a lower imputation error rate (1.24% versus 1.79%). More than 30% of imputation errors occurred in haplotypes enriched in Finland. The frequencies of imputed HLA alleles were highly correlated with clinical-grade HLA allele frequencies and allowed accurate replication of established HLA-disease associations in ∼102 000 biobank participants. The results show that a population-specific reference increases imputation accuracy in a relatively isolated population within Europe and can be successfully applied to biobank-scale genome data collections.
HLA基因是人类基因组中多态性最高的基因，是自身免疫性疾病、移植同种免疫和感染最强的单一遗传易感性因素。基于与等位基因处于连锁不平衡（LD）状态的单核苷酸多态性（SNP）通过等位基因的统计推断进行HLA分型是一种强大的初步筛选工具。由于不同人群之间LD结构不同，HLA分型的准确性可能受益于使分型参考与研究人群相匹配。为了评估在HLA分型中使用特定人群参考的潜在优势，我们构建了一个HLA参考面板，该面板由1150名芬兰人组成，他们拥有5365个在基因组版本之间一致的主要组织相容性复合体区域SNP。我们在一个由213名芬兰受试者组成的独立测试集中，将该面板的准确性与一个欧洲面板进行了评估。我们发现芬兰面板产生的分型错误率更低（分别为1.24%和1.79%）。超过30%的分型错误发生在芬兰富集的单倍型中。推断的HLA等位基因频率与临床级HLA等位基因频率高度相关，并在约102000名生物样本库参与者中能够准确复制已确立的HLA与疾病的关联。结果表明，特定人群参考提高了欧洲相对隔离人群中的分型准确性，并可成功应用于生物样本库规模的基因组数据收集。
