Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex

Background: Neuropsychiatric disorders afflict a large portion of the global population and constitute a significant source of disability worldwide. Although Genome-wide Association Studies (GWAS) have identified many disorder-associated variants, the underlying regulatory mechanisms linking them to disorders remain elusive, especially those involving distant genomic elements. Expression quantitative trait loci (eQTLs) constitute a powerful means of providing this missing link. However, most eQTL studies in human brains have focused exclusively on cis-eQTLs, which link variants to nearby genes (i.e., those within 1 Mb of a variant). A complete understanding of disease etiology requires a clearer understanding of trans-regulatory mechanisms, which, in turn, entails a detailed analysis of the relationships between variants and expression changes in distant genes. Methods: By leveraging large datasets from the PsychENCODE consortium, we conducted a genome-wide survey of trans-eQTLs in the human dorsolateral prefrontal cortex. We also performed colocalization and mediation analyses to identify mediators in trans-regulation and use trans-eQTLs to link GWAS loci to schizophrenia risk genes. Results: We identified -80,000 candidate trans-eQTLs (at FDR<0.25) that influence the expression of -10K target genes (i.e.,trans-eGenes'). We found that many variants associated with these candidate trans-eQTLs overlap with known cis-eQTLs. Moreover, for >60% of these variants (by colocalization), the cis-eQTL's target gene acts as a mediator for the trans-eQTL SNP's effect on the trans-eGene, highlighting examples of cis-mediation as essential for transregulation. Furthermore, many of these colocalized variants fall into a discernable pattern wherein cis-eQTL's target is a transcription factor or RNA-binding protein, which, in turn, targets the gene associated with the candidate trans-eQTL. Finally, we show that trans-regulatory mechanisms provide valuable insights into psychiatric disorders: beyond what had been possible using only cis-eQTLs, we link an additional 23 GWAS loci and 90 risk genes (using colocalization between candidate trans-eQTLs and schizophrenia GWAS loci). Conclusions: We demonstrate that the transcriptional architecture of the human brain is orchestrated by both cisand trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology.

Automated summary

This study investigates the transcriptional regulatory structure of the human brain, revealing the coordination of both cis- and trans-regulatory variants. By analyzing large datasets, the researchers identified candidate trans-eQTLs that influence the expression of target genes and found overlap with known cis-eQTLs. Through colocalization and mediation analyses, they identified mediators in trans-regulation and linked trans-eQTLs to schizophrenia risk genes. The findings demonstrate the importance of trans-regulatory mechanisms in understanding psychiatric disorders.