Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-11-01
|
| Series: | Genome Medicine |
| Online Access: | https://doi.org/10.1186/s13073-022-01133-8 |
| _version_ | 1811304455333740544 |
|---|---|
| author | Shuang Liu Hyejung Won Declan Clarke Nana Matoba Saniya Khullar Yudi Mu Daifeng Wang Mark Gerstein |
| author_facet | Shuang Liu Hyejung Won Declan Clarke Nana Matoba Saniya Khullar Yudi Mu Daifeng Wang Mark Gerstein |
| author_sort | Shuang Liu |
| collection | DOAJ |
| description | 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 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 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. |
| first_indexed | 2024-04-13T08:06:22Z |
| format | Article |
| id | doaj.art-f27667976e18464f80dc9bd617221320 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-13T08:06:22Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-f27667976e18464f80dc9bd6172213202022-12-22T02:55:08ZengBMCGenome Medicine1756-994X2022-11-0114111510.1186/s13073-022-01133-8Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortexShuang Liu0Hyejung Won1Declan Clarke2Nana Matoba3Saniya Khullar4Yudi Mu5Daifeng Wang6Mark Gerstein7Waisman Center, University of Wisconsin – MadisonDepartment of Genetics, University of North Carolina at Chapel HillDepartment of Molecular Biophysics and Biochemistry, Yale UniversityDepartment of Genetics, University of North Carolina at Chapel HillWaisman Center, University of Wisconsin – MadisonDepartment of Statistics, University of Wisconsin – MadisonWaisman Center, University of Wisconsin – MadisonDepartment of Molecular Biophysics and Biochemistry, Yale UniversityAbstract 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 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.https://doi.org/10.1186/s13073-022-01133-8 |
| spellingShingle | Shuang Liu Hyejung Won Declan Clarke Nana Matoba Saniya Khullar Yudi Mu Daifeng Wang Mark Gerstein Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex Genome Medicine |
| title | Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex |
| title_full | Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex |
| title_fullStr | Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex |
| title_full_unstemmed | Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex |
| title_short | Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex |
| title_sort | illuminating links between cis regulators and trans acting variants in the human prefrontal cortex |
| url | https://doi.org/10.1186/s13073-022-01133-8 |
| work_keys_str_mv | AT shuangliu illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex AT hyejungwon illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex AT declanclarke illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex AT nanamatoba illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex AT saniyakhullar illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex AT yudimu illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex AT daifengwang illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex AT markgerstein illuminatinglinksbetweencisregulatorsandtransactingvariantsinthehumanprefrontalcortex |