Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues
Abstract Background Prioritizing genes that underlie complex brain disorders poses a considerable challenge. Despite previous studies have found that they shared symptoms and heterogeneity, it remained difficult to systematically identify the risk genes associated with them. Methods By using the CAG...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-023-01210-6 |
| _version_ | 1827890301958619136 |
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| author | Xingzhong Zhao Liting Song Anyi Yang Zichao Zhang Jinglong Zhang Yucheng T. Yang Xing-Ming Zhao |
| author_facet | Xingzhong Zhao Liting Song Anyi Yang Zichao Zhang Jinglong Zhang Yucheng T. Yang Xing-Ming Zhao |
| author_sort | Xingzhong Zhao |
| collection | DOAJ |
| description | Abstract Background Prioritizing genes that underlie complex brain disorders poses a considerable challenge. Despite previous studies have found that they shared symptoms and heterogeneity, it remained difficult to systematically identify the risk genes associated with them. Methods By using the CAGE (Cap Analysis of Gene Expression) read alignment files for 439 human cell and tissue types (including primary cells, tissues and cell lines) from FANTOM5 project, we predicted enhancer-promoter interactions (EPIs) of 439 cell and tissue types in human, and examined their reliability. Then we evaluated the genetic heritability of 17 diverse brain disorders and behavioral-cognitive phenotypes in each neural cell type, brain region, and developmental stage. Furthermore, we prioritized genes associated with brain disorders and phenotypes by leveraging the EPIs in each neural cell and tissue type, and analyzed their pleiotropy and functionality for different categories of disorders and phenotypes. Finally, we characterized the spatiotemporal expression dynamics of these associated genes in cells and tissues. Results We found that identified EPIs showed activity specificity and network aggregation in cell and tissue types, and enriched TF binding in neural cells played key roles in synaptic plasticity and nerve cell development, i.e., EGR1 and SOX family. We also discovered that most neurological disorders exhibit heritability enrichment in neural stem cells and astrocytes, while psychiatric disorders and behavioral-cognitive phenotypes exhibit enrichment in neurons. Furthermore, our identified genes recapitulated well-known risk genes, which exhibited widespread pleiotropy between psychiatric disorders and behavioral-cognitive phenotypes (i.e., FOXP2), and indicated expression specificity in neural cell types, brain regions, and developmental stages associated with disorders and phenotypes. Importantly, we showed the potential associations of brain disorders with brain regions and developmental stages that have not been well studied. Conclusions Overall, our study characterized the gene-enhancer regulatory networks and genetic mechanisms in the human neural cells and tissues, and illustrated the value of reanalysis of publicly available genomic datasets. |
| first_indexed | 2024-03-12T21:08:16Z |
| format | Article |
| id | doaj.art-a8aec2a04b2f4490b5607d604452a6ae |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-12T21:08:16Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-a8aec2a04b2f4490b5607d604452a6ae2023-07-30T11:21:26ZengBMCGenome Medicine1756-994X2023-07-0115112010.1186/s13073-023-01210-6Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissuesXingzhong Zhao0Liting Song1Anyi Yang2Zichao Zhang3Jinglong Zhang4Yucheng T. Yang5Xing-Ming Zhao6Institute of Science and Technology for Brain-Inspired Intelligence, and Department of Neurology of Zhongshan Hospital, Fudan UniversityInstitute of Science and Technology for Brain-Inspired Intelligence, and Department of Neurology of Zhongshan Hospital, Fudan UniversityInstitute of Science and Technology for Brain-Inspired Intelligence, and Department of Neurology of Zhongshan Hospital, Fudan UniversityInstitute of Science and Technology for Brain-Inspired Intelligence, and Department of Neurology of Zhongshan Hospital, Fudan UniversityInstitute of Science and Technology for Brain-Inspired Intelligence, and Department of Neurology of Zhongshan Hospital, Fudan UniversityInstitute of Science and Technology for Brain-Inspired Intelligence, and Department of Neurology of Zhongshan Hospital, Fudan UniversityInstitute of Science and Technology for Brain-Inspired Intelligence, and Department of Neurology of Zhongshan Hospital, Fudan UniversityAbstract Background Prioritizing genes that underlie complex brain disorders poses a considerable challenge. Despite previous studies have found that they shared symptoms and heterogeneity, it remained difficult to systematically identify the risk genes associated with them. Methods By using the CAGE (Cap Analysis of Gene Expression) read alignment files for 439 human cell and tissue types (including primary cells, tissues and cell lines) from FANTOM5 project, we predicted enhancer-promoter interactions (EPIs) of 439 cell and tissue types in human, and examined their reliability. Then we evaluated the genetic heritability of 17 diverse brain disorders and behavioral-cognitive phenotypes in each neural cell type, brain region, and developmental stage. Furthermore, we prioritized genes associated with brain disorders and phenotypes by leveraging the EPIs in each neural cell and tissue type, and analyzed their pleiotropy and functionality for different categories of disorders and phenotypes. Finally, we characterized the spatiotemporal expression dynamics of these associated genes in cells and tissues. Results We found that identified EPIs showed activity specificity and network aggregation in cell and tissue types, and enriched TF binding in neural cells played key roles in synaptic plasticity and nerve cell development, i.e., EGR1 and SOX family. We also discovered that most neurological disorders exhibit heritability enrichment in neural stem cells and astrocytes, while psychiatric disorders and behavioral-cognitive phenotypes exhibit enrichment in neurons. Furthermore, our identified genes recapitulated well-known risk genes, which exhibited widespread pleiotropy between psychiatric disorders and behavioral-cognitive phenotypes (i.e., FOXP2), and indicated expression specificity in neural cell types, brain regions, and developmental stages associated with disorders and phenotypes. Importantly, we showed the potential associations of brain disorders with brain regions and developmental stages that have not been well studied. Conclusions Overall, our study characterized the gene-enhancer regulatory networks and genetic mechanisms in the human neural cells and tissues, and illustrated the value of reanalysis of publicly available genomic datasets.https://doi.org/10.1186/s13073-023-01210-6Cis-regulatory elementEnhancer-promoter interactionBain disorderHeritability |
| spellingShingle | Xingzhong Zhao Liting Song Anyi Yang Zichao Zhang Jinglong Zhang Yucheng T. Yang Xing-Ming Zhao Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues Genome Medicine Cis-regulatory element Enhancer-promoter interaction Bain disorder Heritability |
| title | Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues |
| title_full | Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues |
| title_fullStr | Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues |
| title_full_unstemmed | Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues |
| title_short | Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues |
| title_sort | prioritizing genes associated with brain disorders by leveraging enhancer promoter interactions in diverse neural cells and tissues |
| topic | Cis-regulatory element Enhancer-promoter interaction Bain disorder Heritability |
| url | https://doi.org/10.1186/s13073-023-01210-6 |
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