Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes
Abstract Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-...
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| Format: | Article |
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Nature Portfolio
2024-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52356-9 |
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| author | Erping Long Jinhu Yin Ju Hye Shin Yuyan Li Bolun Li Alexander Kane Harsh Patel Xinti Sun Cong Wang Thong Luong Jun Xia Younghun Han Jinyoung Byun Tongwu Zhang Wei Zhao Maria Teresa Landi Nathaniel Rothman Qing Lan Yoon Soo Chang Fulong Yu Christopher I. Amos Jianxin Shi Jin Gu Lee Eun Young Kim Jiyeon Choi |
| author_facet | Erping Long Jinhu Yin Ju Hye Shin Yuyan Li Bolun Li Alexander Kane Harsh Patel Xinti Sun Cong Wang Thong Luong Jun Xia Younghun Han Jinyoung Byun Tongwu Zhang Wei Zhao Maria Teresa Landi Nathaniel Rothman Qing Lan Yoon Soo Chang Fulong Yu Christopher I. Amos Jianxin Shi Jin Gu Lee Eun Young Kim Jiyeon Choi |
| author_sort | Erping Long |
| collection | DOAJ |
| description | Abstract Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function. |
| format | Article |
| id | doaj-art-c8946b388f1b4930819dd2bcbe00021c |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c8946b388f1b4930819dd2bcbe00021c2025-08-20T02:22:29ZengNature PortfolioNature Communications2041-17232024-09-0115111610.1038/s41467-024-52356-9Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genesErping Long0Jinhu Yin1Ju Hye Shin2Yuyan Li3Bolun Li4Alexander Kane5Harsh Patel6Xinti Sun7Cong Wang8Thong Luong9Jun Xia10Younghun Han11Jinyoung Byun12Tongwu Zhang13Wei Zhao14Maria Teresa Landi15Nathaniel Rothman16Qing Lan17Yoon Soo Chang18Fulong Yu19Christopher I. Amos20Jianxin Shi21Jin Gu Lee22Eun Young Kim23Jiyeon Choi24Division of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDepartment of Internal Medicine, Yonsei University College of MedicineInstitute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteInstitute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDepartment of Biomedical Sciences, Creighton UniversityInstitute for Clinical and Translational Research, Baylor College of MedicineInstitute for Clinical and Translational Research, Baylor College of MedicineDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDepartment of Internal Medicine, Yonsei University College of MedicineGuangzhou National Laboratory, Guangzhou International Bio IslandInstitute for Clinical and Translational Research, Baylor College of MedicineDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDepartment of Thoracic and Cardiovascular Surgery, Yonsei University College of MedicineDepartment of Internal Medicine, Yonsei University College of MedicineDivision of Cancer Epidemiology and Genetics, National Cancer InstituteAbstract Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function.https://doi.org/10.1038/s41467-024-52356-9 |
| spellingShingle | Erping Long Jinhu Yin Ju Hye Shin Yuyan Li Bolun Li Alexander Kane Harsh Patel Xinti Sun Cong Wang Thong Luong Jun Xia Younghun Han Jinyoung Byun Tongwu Zhang Wei Zhao Maria Teresa Landi Nathaniel Rothman Qing Lan Yoon Soo Chang Fulong Yu Christopher I. Amos Jianxin Shi Jin Gu Lee Eun Young Kim Jiyeon Choi Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes Nature Communications |
| title | Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes |
| title_full | Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes |
| title_fullStr | Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes |
| title_full_unstemmed | Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes |
| title_short | Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes |
| title_sort | context aware single cell multiomics approach identifies cell type specific lung cancer susceptibility genes |
| url | https://doi.org/10.1038/s41467-024-52356-9 |
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