Integrative genomics sheds light on the immunogenetics of tuberculosis in cattle

Mycobacterium bovis causes bovine tuberculosis (bTB), an infectious disease of cattle that represents a zoonotic threat to humans. Research has shown that the peripheral blood (PB) transcriptome is perturbed during bTB disease but the genomic architecture underpinning this transcriptional response remains poorly understood. Here, we analyse PB transcriptomics data from 63 control and 60 confirmed M. bovis infected animals and detect 2,592 differently expressed genes perturbing multiple immune response pathways. Leveraging imputed genome-wide SNP data, we characterise thousands of cis­-expression quantitative trait loci (eQTLs) and show that the PB transcriptome is substantially impacted by intrapopulation genomic variation during M. bovis infection. Integrating our cis-eQTL data with bTB susceptibility GWAS summary statistics, we perform a transcriptome-wide association study and identify 132 functionally relevant genes (including RGS10, GBP4, TREML2, and RELT) and provide important new omics data for understanding the host response to mycobacterial infections that cause tuberculosis in mammals.牛分枝杆菌（Mycobacterium bovis）可引发牛结核病（bovine tuberculosis, bTB），这是一种可对人类构成人畜共患威胁的牛传染性疾病。已有研究表明，牛结核病感染期间宿主外周血（peripheral blood, PB）转录组（transcriptome）会出现失调，但支撑该转录应答的基因组架构仍未得到充分阐明。本研究对63头对照动物与60头经确诊的牛分枝杆菌感染动物的PB转录组学数据展开分析，共检测到2592个差异表达基因（differently expressed genes），这些基因可扰乱多条免疫应答通路。研究人员借助经基因型填充的全基因组单核苷酸多态性（single nucleotide polymorphism, SNP）数据，对数千个顺式表达数量性状位点（cis-expression quantitative trait loci, eQTLs）进行了特征解析，并证实牛分枝杆菌感染期间，种群内基因组变异可对宿主PB转录组产生显著影响。本研究将顺式eQTL数据与牛结核病易感性状的全基因组关联分析（Genome-Wide Association Study, GWAS）汇总统计量进行整合，开展了全转录组关联研究（transcriptome-wide association study），最终鉴定出132个功能相关的基因（包括RGS10、GBP4、TREML2及RELT），并为理解宿主对可引发哺乳动物结核病的分枝杆菌感染的应答机制提供了重要的新型组学数据。