Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer
Abstract Genome-wide association studies have identified thousands of genetic variants associated with non-small cell lung cancer (NSCLC), however, it is still challenging to determine the causal variants and to improve disease risk prediction. Here, we applied massively parallel reporter assays to...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56725-w |
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| author | Congcong Chen Yang Li Yayun Gu Qiqi Zhai Songwei Guo Jun Xiang Yuan Xie Mingxing An Chenmeijie Li Na Qin Yanan Shi Liu Yang Jun Zhou Xianfeng Xu Ziye Xu Kai Wang Meng Zhu Yue Jiang Yuanlin He Jing Xu Rong Yin Liang Chen Lin Xu Juncheng Dai Guangfu Jin Zhibin Hu Cheng Wang Hongxia Ma Hongbing Shen |
| author_facet | Congcong Chen Yang Li Yayun Gu Qiqi Zhai Songwei Guo Jun Xiang Yuan Xie Mingxing An Chenmeijie Li Na Qin Yanan Shi Liu Yang Jun Zhou Xianfeng Xu Ziye Xu Kai Wang Meng Zhu Yue Jiang Yuanlin He Jing Xu Rong Yin Liang Chen Lin Xu Juncheng Dai Guangfu Jin Zhibin Hu Cheng Wang Hongxia Ma Hongbing Shen |
| author_sort | Congcong Chen |
| collection | DOAJ |
| description | Abstract Genome-wide association studies have identified thousands of genetic variants associated with non-small cell lung cancer (NSCLC), however, it is still challenging to determine the causal variants and to improve disease risk prediction. Here, we applied massively parallel reporter assays to perform NSCLC variant-to-function mapping at scale. A total of 1249 candidate variants were evaluated, and 30 potential causal variants within 12 loci were identified. Accordingly, we proposed three genetic architectures underlying NSCLC susceptibility: multiple causal variants in a single haplotype block (e.g. 4q22.1), multiple causal variants in multiple haplotype blocks (e.g. 5p15.33), and a single causal variant (e.g. 20q11.23). We developed a modified polygenic risk score using the potential causal variants from Chinese populations, improving the performance of risk prediction in 450,821 Europeans from the UK Biobank. Our findings not only augment the understanding of the genetic architecture underlying NSCLC susceptibility but also provide strategy to advance NSCLC risk stratification. |
| format | Article |
| id | doaj-art-1b6afcf814f04198ab97daca7cc0f7d2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1b6afcf814f04198ab97daca7cc0f7d22025-02-09T12:44:18ZengNature PortfolioNature Communications2041-17232025-02-0116111610.1038/s41467-025-56725-wMassively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancerCongcong Chen0Yang Li1Yayun Gu2Qiqi Zhai3Songwei Guo4Jun Xiang5Yuan Xie6Mingxing An7Chenmeijie Li8Na Qin9Yanan Shi10Liu Yang11Jun Zhou12Xianfeng Xu13Ziye Xu14Kai Wang15Meng Zhu16Yue Jiang17Yuanlin He18Jing Xu19Rong Yin20Liang Chen21Lin Xu22Juncheng Dai23Guangfu Jin24Zhibin Hu25Cheng Wang26Hongxia Ma27Hongbing Shen28Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical UniversityDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Key Laboratory of Molecular and Translational Cancer Research, Department of Thoracic Surgery Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer HospitalDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Key Laboratory of Molecular and Translational Cancer Research, Department of Thoracic Surgery Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer HospitalDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityAbstract Genome-wide association studies have identified thousands of genetic variants associated with non-small cell lung cancer (NSCLC), however, it is still challenging to determine the causal variants and to improve disease risk prediction. Here, we applied massively parallel reporter assays to perform NSCLC variant-to-function mapping at scale. A total of 1249 candidate variants were evaluated, and 30 potential causal variants within 12 loci were identified. Accordingly, we proposed three genetic architectures underlying NSCLC susceptibility: multiple causal variants in a single haplotype block (e.g. 4q22.1), multiple causal variants in multiple haplotype blocks (e.g. 5p15.33), and a single causal variant (e.g. 20q11.23). We developed a modified polygenic risk score using the potential causal variants from Chinese populations, improving the performance of risk prediction in 450,821 Europeans from the UK Biobank. Our findings not only augment the understanding of the genetic architecture underlying NSCLC susceptibility but also provide strategy to advance NSCLC risk stratification.https://doi.org/10.1038/s41467-025-56725-w |
| spellingShingle | Congcong Chen Yang Li Yayun Gu Qiqi Zhai Songwei Guo Jun Xiang Yuan Xie Mingxing An Chenmeijie Li Na Qin Yanan Shi Liu Yang Jun Zhou Xianfeng Xu Ziye Xu Kai Wang Meng Zhu Yue Jiang Yuanlin He Jing Xu Rong Yin Liang Chen Lin Xu Juncheng Dai Guangfu Jin Zhibin Hu Cheng Wang Hongxia Ma Hongbing Shen Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer Nature Communications |
| title | Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer |
| title_full | Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer |
| title_fullStr | Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer |
| title_full_unstemmed | Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer |
| title_short | Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer |
| title_sort | massively parallel variant to function mapping determines functional regulatory variants of non small cell lung cancer |
| url | https://doi.org/10.1038/s41467-025-56725-w |
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