Trans-eQTLs Can Be Used to Identify Tissue-Specific Gene Regulatory Networks

Previous high-throughput screening studies have indicated that trans-eQTLs tend to be tissue-specific. This study investigates whether this feature can be used to identify tissue-specific gene regulatory networks. eQTL data for 19,960 genes were obtained from the eQTLGen study. Next, eQTLs displaying both cis- and trans-regulatory effects (p < 5 × 10^-8) were selected, and the association between their corresponding genes was examined by Mendelian randomization. The findings were further validated using eQTL data from the INTERVAL study. The trans-regulatory impact of 138 genes on 342 genes was detected (p < 5 × 10^-8). The majority of the identified gene-pairs were aggregated into networks with scale-free topology. An examination of the function of genes indicates they are involved in immune processes. The hub genes primarily shared transcription regulation activity and were associated with blood cell traits. The hub gene, DDAH2, impacted several metabolic and autoimmune disorders. On average, a gene in the network was under the regulatory control of 34 cis-eQTLs and 6 trans-eQTLs, and genes with higher heritabilities tended to exert higher regulatory impacts. This study reports tissue-specific gene regulatory networks can be detected by investigating their genomic underpinnings. The identified networks displayed scale-free topology, indicating that hub genes within a network could be targeted to correct abnormalities.