| Autor: |
Shuang Liu, Hyejung Won, Declan Clarke, Nana Matoba, Saniya Khullar, Yudi Mu, Daifeng Wang, Mark Gerstein |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Genome Medicine, Vol 14, Iss 1, Pp 1-15 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1756-994X |
| DOI: |
10.1186/s13073-022-01133-8 |
| Popis: |
Abstract 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 FDR60% 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 trans-regulation. 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 cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology. |
| Databáze: |
Directory of Open Access Journals |
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