Introduction: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and informs public health interventions. Methods: We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort. Results: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr Virus (EBV), Varicella Zoster Virus (VZV), Human Herpes virus 7, (HHV7) and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci associated with viral antibody response (P<5.0×10^-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, as well as CXCR5 (11q23.3) and TBKBP1 (17q21.32) for human herpesvirus 7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P=5.0×10^-15 (MCV), NTN5: P=1.1×10^-9 (BKV), and P2RY13: P=1.1×10^-8 (Epstein-Barr virus nuclear antigen). We also demonstrated pleiotropy between viral response genes and complex diseases, such as C4A expression in varicella zoster virus and schizophrenia. Conclusions: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.

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宿主对常见病毒感染的免疫反应中涉及的遗传因素的概况

简介：人类和病毒共同进化了数千年，形成了复杂的宿主遗传结构。了解病毒感染免疫反应的遗传机制可深入了解疾病病因，并为公共卫生干预提供依据。方法：我们进行了一项全面的研究，包括全基因组和转录组范围的关联分析，以使用来自英国Biobank队列的7924名欧洲血统参与者的血清学数据，鉴定与免疫球蛋白G抗体对16种病毒的28种抗原反应相关的遗传基因座。结果：人类白细胞抗原（HLA）II类区域中的信号主导了病毒抗体应答的格局，有40个独立的基因座和14个独立的经典等位基因，其中7个在整个病毒家族中表现出多效作用。我们确定了与血清反应性相关的特定氨基酸（AA）残基，这是针对爱泼斯坦-巴尔病毒（EBV），水痘带状疱疹病毒的DRβ1内11、13、71和74位的一系列AA位置中最强的关联（ （VZV），人类疱疹病毒7（HHV7）和默克尔细胞多瘤病毒（MCV）。全基因组关联分析发现与病毒抗体应答相关7新颖的遗传位点（P <5.0×10 ^-8），包括FUT2（19q13.33）人多瘤病毒BK（BKV），STING1MCV （5q31.2），人疱疹病毒7的CXCR5（11q23.3）和TBKBP1（17q21.32）。转录组范围的关联分析确定了114个与病毒感染反应相关的基因，其中12个位于HLA区域之外，包括ECSCR：P ＝ 5.0×10 ^-15（MCV），NTN5：P ＝ 1.1×10 ^-9（BKV）和P2RY13：P ＝ 1.1×10 ^-8（Epstein-Barr病毒核抗原）。我们还证明了病毒反应基因与复杂疾病（如水痘带状疱疹病毒和精神分裂症中C4A表达）之间的多效性。结论：我们的研究证实了HLA区域在宿主对病毒感染的反应中的重要性，并阐明了HLA以外新的遗传决定因素，这些因素决定了宿主与病毒之间的相互作用。