Kvamme Jarred, Badsha Md Bahadur, Martin Evan A, Wu Jiayu, Wang Xiaoyue, Fu Audrey Qiuyan
The Bioinformatics and Computational Biology Program, University of Idaho, Moscow, ID 83844, USA.
Institute for Modeling Collaboration and Innovation, University of Idaho, Moscow, ID 83844, USA.
Genetics. 2025 Jun 4;230(2). doi: 10.1093/genetics/iyaf064.
Expression quantitative trait loci (eQTLs) have been identified for most genes in the human genome across tissues and cell types. While most of the eQTLs are near (i.e. cis) the associated genes on the linear genome, some can be far away or on different chromosomes (i.e. trans), with the regulatory mechanisms largely unknown. Here, we study regulation by eQTLs of their cis- and trans-genes across nearly 50 tissues and cell types, taking a causal network inference approach and leveraging the principle of Mendelian randomization. Specifically, we constructed trios consisting of an eQTL, its cis-gene and trans-gene. We then inferred the regulatory relationships, using the eQTL as an instrumental variable and accounting for confounding variables. We identify multiple types of regulatory networks for trios: across all the tissues, more than half of the trios are inferred to be conditionally independent, where the two genes are conditionally independent given the genotype of the eQTL (gene1←eQTL→gene2). Around 1.5% of the trios are inferred to be mediation (eQTL→mediator→target), around 1.3% fully connected among the three nodes, and just a handful v-structures (eQTL→gene1←gene2). The identifications are generally consistent with the statistical dependence patterns of each trio. Genes in trios of different regulatory types exhibit distinct functional enrichments. Interestingly, many mediation trios have the trans-gene as the mediator. Existing transcription factor databases and HiC data for genome spatial structure provide additional support for long-range cis-acting and trans-acting in some of the inferred trans-gene mediation trios.
在各种组织和细胞类型中，人类基因组中的大多数基因都已鉴定出表达数量性状基因座（eQTL）。虽然大多数eQTL在线性基因组上与相关基因相邻（即顺式），但有些可能相距甚远或位于不同染色体上（即反式），其调控机制大多未知。在这里，我们采用因果网络推断方法并利用孟德尔随机化原理，研究了近50种组织和细胞类型中eQTL对其顺式和反式基因的调控。具体而言，我们构建了由一个eQTL、其顺式基因和反式基因组成的三联体。然后，我们以eQTL作为工具变量并考虑混杂变量，推断调控关系。我们识别出三联体的多种调控网络类型：在所有组织中，超过一半的三联体被推断为条件独立，即给定eQTL的基因型时，两个基因是条件独立的（基因1←eQTL→基因2）。约1.5%的三联体被推断为中介作用（eQTL→中介物→靶标），约1.3%在三个节点之间完全连接，只有少数是v结构（eQTL→基因1←基因2）。这些识别结果通常与每个三联体的统计依赖模式一致。不同调控类型的三联体中的基因表现出不同的功能富集。有趣的是，许多中介三联体以反式基因作为中介物。现有的转录因子数据库和基因组空间结构的HiC数据为一些推断出的反式基因中介三联体中的远程顺式作用和反式作用提供了额外支持。
