Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.
Institute of Clinical Human Genetics, University Hospital Regensburg, 93053 Regensburg, Germany.
Cells. 2021 Sep 12;10(9):2395. doi: 10.3390/cells10092395.
Elucidating the role of genetic variation in the regulation of gene expression is key to understanding the pathobiology of complex diseases which, in consequence, is crucial in devising targeted treatment options. Expression quantitative trait locus (eQTL) analysis correlates a genetic variant with the strength of gene expression, thus defining thousands of regulated genes in a multitude of human cell types and tissues. Some eQTL may not act independently of each other but instead may be regulated in a coordinated fashion by seemingly independent genetic variants. To address this issue, we combined the approaches of eQTL analysis and colocalization studies. Gene expression was determined in datasets comprising 49 tissues from the Genotype-Tissue Expression (GTEx) project. From about 33,000 regulated genes, over 14,000 were found to be co-regulated in pairs and were assembled across all tissues to almost 15,000 unique clusters containing up to nine regulated genes affected by the same eQTL signal. The distance of co-regulated eGenes was, on average, 112 kilobase pairs. Of 713 genes known to express clinical symptoms upon haploinsufficiency, 231 (32.4%) are part of at least one of the identified clusters. This calls for caution should treatment approaches aim at an upregulation of a haploinsufficient gene. In conclusion, we present an unbiased approach to identifying co-regulated genes in and across multiple tissues. Knowledge of such common effects is crucial to appreciate implications on biological pathways involved, specifically when a treatment option targets a co-regulated disease gene.
阐明遗传变异在基因表达调控中的作用是理解复杂疾病病理生物学的关键，因此，设计针对特定疾病的治疗方案至关重要。表达数量性状基因座（eQTL）分析将遗传变异与基因表达强度相关联，从而定义了多种人类细胞类型和组织中数千个受调控的基因。一些 eQTL 可能不是相互独立作用的，而是可能通过看似独立的遗传变异以协调的方式进行调控。为了解决这个问题，我们结合了 eQTL 分析和共定位研究的方法。在包含来自 Genotype-Tissue Expression (GTEx) 项目的 49 种组织的数据集，我们测定了基因表达。在大约 33000 个受调控的基因中，有超过 14000 个被发现成对共调控，并在所有组织中组装成近 15000 个独特的簇，其中包含多达 9 个受相同 eQTL 信号影响的受调控基因。共调控 eGenes 的平均距离为 112 千碱基对。在已知单倍体不足会表达临床症状的 713 个基因中，有 231 个（32.4%）至少是已确定的簇中的一个的一部分。如果治疗方法旨在上调单倍体不足的基因，这就需要谨慎对待。总之，我们提出了一种在多个组织中识别共调控基因的无偏方法。了解这些共同效应对于理解所涉及的生物学途径的影响至关重要，特别是当治疗方案针对共调控的疾病基因时。
