Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases
Abstract Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between the eye and brain, we integrated bulk and single-cell multiomic pr...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03243-4 |
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| author | Yunlong Ma Dingping Jiang Jingjing Li Gongwei Zheng Yao Deng Xuanxuan Gou Shuaishuai Gao Cheng Chen Yijun Zhou Yaru Zhang Chunyu Deng Yinghao Yao Haijun Han Jianzhong Su |
| author_facet | Yunlong Ma Dingping Jiang Jingjing Li Gongwei Zheng Yao Deng Xuanxuan Gou Shuaishuai Gao Cheng Chen Yijun Zhou Yaru Zhang Chunyu Deng Yinghao Yao Haijun Han Jianzhong Su |
| author_sort | Yunlong Ma |
| collection | DOAJ |
| description | Abstract Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between the eye and brain, we integrated bulk and single-cell multiomic profiles with GWAS summary statistics for eight neuropsychiatric and five ocular diseases. Our analysis uncovered five latent factors explaining 61.7% of the genetic variance across these 13 diseases, revealing diverse correlational patterns among them. We identified 45 pleiotropic loci with 91 candidate genes that contribute to disease risk. By integrating GWAS and single-cell profiles, we implicated excitatory neurons and microglia as key contributors in the eye-brain connections. Polygenic enrichment analysis further identified 15 pleiotropic regulons in excitatory neurons and 16 in microglia that were linked to comorbid conditions. Functionally, excitatory neuron-specific regulons were involved in axon guidance and synaptic activity, while microglia-specific regulons were associated with immune response and cell activation. In sum, these findings underscore the genetic link between psychiatric disorders and ocular diseases. |
| format | Article |
| id | doaj-art-d06836c44d0d418bb617f1f2d0c5907a |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-d06836c44d0d418bb617f1f2d0c5907a2025-01-26T12:53:40ZengNature Publishing GroupTranslational Psychiatry2158-31882025-01-0115111910.1038/s41398-025-03243-4Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseasesYunlong Ma0Dingping Jiang1Jingjing Li2Gongwei Zheng3Yao Deng4Xuanxuan Gou5Shuaishuai Gao6Cheng Chen7Yijun Zhou8Yaru Zhang9Chunyu Deng10Yinghao Yao11Haijun Han12Jianzhong Su13Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityInstitute of Genomic Medicine, Wenzhou Medical UniversitySchool of Medicine, Hangzhou City UniversityOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical UniversityAbstract Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between the eye and brain, we integrated bulk and single-cell multiomic profiles with GWAS summary statistics for eight neuropsychiatric and five ocular diseases. Our analysis uncovered five latent factors explaining 61.7% of the genetic variance across these 13 diseases, revealing diverse correlational patterns among them. We identified 45 pleiotropic loci with 91 candidate genes that contribute to disease risk. By integrating GWAS and single-cell profiles, we implicated excitatory neurons and microglia as key contributors in the eye-brain connections. Polygenic enrichment analysis further identified 15 pleiotropic regulons in excitatory neurons and 16 in microglia that were linked to comorbid conditions. Functionally, excitatory neuron-specific regulons were involved in axon guidance and synaptic activity, while microglia-specific regulons were associated with immune response and cell activation. In sum, these findings underscore the genetic link between psychiatric disorders and ocular diseases.https://doi.org/10.1038/s41398-025-03243-4 |
| spellingShingle | Yunlong Ma Dingping Jiang Jingjing Li Gongwei Zheng Yao Deng Xuanxuan Gou Shuaishuai Gao Cheng Chen Yijun Zhou Yaru Zhang Chunyu Deng Yinghao Yao Haijun Han Jianzhong Su Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases Translational Psychiatry |
| title | Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases |
| title_full | Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases |
| title_fullStr | Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases |
| title_full_unstemmed | Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases |
| title_short | Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases |
| title_sort | systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases |
| url | https://doi.org/10.1038/s41398-025-03243-4 |
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