Transcription factors operate across disease loci: EBNA2 in autoimmunity. Homo sapiens

Explaining the genetics of many diseases is challenging because most associations localize to regulatory regions. We present a novel computational method for discovering disease-driving mechanisms acting across multiple disease-associated, non-coding genomic regions. Application to a matrix of 213 phenotypes and 1,544 transcription factor (TF) binding datasets identifies 2,264 significant associations for hundreds of TFs in 92 phenotypes, including prostate and breast cancers. Strikingly, nearly half of the systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and 24 human TFs, revealing an important gene-environment interaction. EBNA2-anchored associations also exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal autoimmune variants support a genetic mechanism of pathogenesis centered on EBNA2. Our results nominate mechanisms operating across disease risk loci, suggesting new paradigms of disease origins. Overall design: To identify differentially expressed genes associated with EBV infection.

阐明诸多疾病的遗传机制颇具挑战，这是因为绝大多数疾病关联位点均定位于基因组调控区域。本研究提出一种全新的计算方法，用于挖掘跨多个疾病相关非编码基因组区域发挥作用的疾病驱动机制。将该方法应用于包含213种表型与1544个转录因子（Transcription Factor, TF）结合数据集的矩阵后，我们在包括前列腺癌、乳腺癌在内的92种表型中，鉴定出数百个转录因子对应的2264个显著关联。值得注意的是，近半数系统性红斑狼疮（systemic lupus erythematosus）风险位点均被EB病毒（Epstein-Barr virus）EBNA2蛋白与24个人类转录因子结合，这揭示了一种重要的基因-环境交互作用。以EBNA2为锚定的关联同样存在于多发性硬化、类风湿关节炎、炎症性肠病、1型糖尿病、幼年特发性关节炎以及乳糜泻中。在疑似致病的自身免疫变异位点上，存在等位基因依赖性DNA结合及其对基因表达的下游调控效应的相关实例，这支持了以EBNA2为核心的发病遗传机制。本研究结果提出了跨疾病风险位点发挥作用的机制，为疾病起源提供了全新的研究范式。整体实验设计：用于鉴定与EB病毒感染相关的差异表达基因。