Systematic fine-mapping and functional studies of prostate cancer risk variants
Summary: To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants remain elusive. Identification of causal variants and their targets from association signals is complicated by high linkage disequilib...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223005746 |
| _version_ | 1797850458411237376 |
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| author | Yuyang Qian Jianhua Wang Bo Wang Wenbin Wang Peng Li Zhenhao Zhao Yuan Jiang He Ren Dandan Huang Yang Yang Zhongfang Zhao Lei Zhang Jiandang Shi Mulin Jun Li Wange Lu |
| author_facet | Yuyang Qian Jianhua Wang Bo Wang Wenbin Wang Peng Li Zhenhao Zhao Yuan Jiang He Ren Dandan Huang Yang Yang Zhongfang Zhao Lei Zhang Jiandang Shi Mulin Jun Li Wange Lu |
| author_sort | Yuyang Qian |
| collection | DOAJ |
| description | Summary: To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants remain elusive. Identification of causal variants and their targets from association signals is complicated by high linkage disequilibrium and limited availability of functional genomics data for specific tissue/cell types. Here, we integrated statistical fine-mapping and functional annotation from prostate-specific epigenomic profiles, 3D genome features, and quantitative trait loci data to distinguish causal variants from associations and identify target genes. Our fine-mapping analysis yielded 3,395 likely causal variants, and multiscale functional annotation linked them to 487 target genes. We prioritized rs10486567 as a genome-wide top-ranked SNP and predicted HOTTIP as its target. Deletion of the rs10486567-associated enhancer in prostate cancer cells decreased their capacity for invasive migration. HOTTIP overexpression in enhancer-KO cell lines rescued defective invasive migration. Furthermore, we found that rs10486567 regulates HOTTIP through allele-specific long-range chromatin interaction. |
| first_indexed | 2024-04-09T19:01:28Z |
| format | Article |
| id | doaj.art-bec4d6fa7aef4208bca3f857105ce0bd |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-09T19:01:28Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-bec4d6fa7aef4208bca3f857105ce0bd2023-04-08T05:14:07ZengElsevieriScience2589-00422023-04-01264106497Systematic fine-mapping and functional studies of prostate cancer risk variantsYuyang Qian0Jianhua Wang1Bo Wang2Wenbin Wang3Peng Li4Zhenhao Zhao5Yuan Jiang6He Ren7Dandan Huang8Yang Yang9Zhongfang Zhao10Lei Zhang11Jiandang Shi12Mulin Jun Li13Wange Lu14State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaDepartment of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaCenter for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Huangdao District, Qingdao 266000, ChinaDepartment of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China; Corresponding authorDepartment of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Corresponding authorState Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China; Corresponding authorSummary: To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants remain elusive. Identification of causal variants and their targets from association signals is complicated by high linkage disequilibrium and limited availability of functional genomics data for specific tissue/cell types. Here, we integrated statistical fine-mapping and functional annotation from prostate-specific epigenomic profiles, 3D genome features, and quantitative trait loci data to distinguish causal variants from associations and identify target genes. Our fine-mapping analysis yielded 3,395 likely causal variants, and multiscale functional annotation linked them to 487 target genes. We prioritized rs10486567 as a genome-wide top-ranked SNP and predicted HOTTIP as its target. Deletion of the rs10486567-associated enhancer in prostate cancer cells decreased their capacity for invasive migration. HOTTIP overexpression in enhancer-KO cell lines rescued defective invasive migration. Furthermore, we found that rs10486567 regulates HOTTIP through allele-specific long-range chromatin interaction.http://www.sciencedirect.com/science/article/pii/S2589004223005746GeneticsCancerGenomics |
| spellingShingle | Yuyang Qian Jianhua Wang Bo Wang Wenbin Wang Peng Li Zhenhao Zhao Yuan Jiang He Ren Dandan Huang Yang Yang Zhongfang Zhao Lei Zhang Jiandang Shi Mulin Jun Li Wange Lu Systematic fine-mapping and functional studies of prostate cancer risk variants iScience Genetics Cancer Genomics |
| title | Systematic fine-mapping and functional studies of prostate cancer risk variants |
| title_full | Systematic fine-mapping and functional studies of prostate cancer risk variants |
| title_fullStr | Systematic fine-mapping and functional studies of prostate cancer risk variants |
| title_full_unstemmed | Systematic fine-mapping and functional studies of prostate cancer risk variants |
| title_short | Systematic fine-mapping and functional studies of prostate cancer risk variants |
| title_sort | systematic fine mapping and functional studies of prostate cancer risk variants |
| topic | Genetics Cancer Genomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223005746 |
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