Dey Kushal K, Gazal Steven, van de Geijn Bryce, Kim Samuel Sungil, Nasser Joseph, Engreitz Jesse M, Price Alkes L
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
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Cell Genom. 2022 Jul 13;2(7). doi: 10.1016/j.xgen.2022.100145.
We assess contributions to autoimmune disease of genes whose regulation is driven by enhancer regions (enhancer-related) and genes that regulate other genes in (candidate master-regulator). We link these genes to SNPs using several SNP-to-gene (S2G) strategies and apply heritability analyses to draw three conclusions about 11 autoimmune/blood-related diseases/traits. First, several characterizations of enhancer-related genes using functional genomics data are informative for autoimmune disease heritability after conditioning on a broad set of regulatory annotations. Second, candidate master-regulator genes defined using -eQTL in blood are also conditionally informative for autoimmune disease heritability. Third, integrating enhancer-related and master-regulator gene sets with protein-protein interaction (PPI) network information magnified their disease signal. The resulting PPI-enhancer gene score produced >2-fold stronger heritability signal and >2-fold stronger enrichment for drug targets, compared with the recently proposed enhancer domain score. In each case, functionally informed S2G strategies produced 4.1- to 13-fold stronger disease signals than conventional window-based strategies.
我们评估了由增强子区域驱动其调控的基因（与增强子相关）以及调控其他基因的基因（候选主调控因子）对自身免疫性疾病的贡献。我们使用多种单核苷酸多态性到基因（S2G）策略将这些基因与单核苷酸多态性（SNP）联系起来，并应用遗传力分析得出关于11种自身免疫/血液相关疾病/性状的三个结论。首先，在以广泛的调控注释为条件后，使用功能基因组学数据对与增强子相关的基因进行的几种表征对于自身免疫性疾病遗传力具有参考价值。其次，在血液中使用表达定量性状位点（eQTL）定义的候选主调控因子基因对于自身免疫性疾病遗传力也具有条件参考价值。第三，将与增强子相关的基因集和主调控因子基因集与蛋白质-蛋白质相互作用（PPI）网络信息整合，放大了它们的疾病信号。与最近提出的增强子结构域评分相比，所得的PPI-增强子基因评分产生了>2倍更强的遗传力信号和>2倍更强的药物靶点富集。在每种情况下，功能知情的S2G策略产生的疾病信号比传统的基于窗口的策略强4.1至13倍。
