Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations
Abstract Background The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-023-01156-9 |
| _version_ | 1811175754557292544 |
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| author | Junyi Xin Mulong Du Dongying Gu Kewei Jiang Mengyun Wang Mingjuan Jin Yeting Hu Shuai Ben Silu Chen Wei Shao Shuwei Li Haiyan Chu Linjun Zhu Chen Li Kun Chen Kefeng Ding Zhengdong Zhang Hongbing Shen Meilin Wang |
| author_facet | Junyi Xin Mulong Du Dongying Gu Kewei Jiang Mengyun Wang Mingjuan Jin Yeting Hu Shuai Ben Silu Chen Wei Shao Shuwei Li Haiyan Chu Linjun Zhu Chen Li Kun Chen Kefeng Ding Zhengdong Zhang Hongbing Shen Meilin Wang |
| author_sort | Junyi Xin |
| collection | DOAJ |
| description | Abstract Background The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. Methods A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. Results In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (P trend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. Conclusions In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer. |
| first_indexed | 2024-04-10T19:41:02Z |
| format | Article |
| id | doaj.art-7d08ab44d2ae4b52b6212ff1bad5e83b |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-10T19:41:02Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-7d08ab44d2ae4b52b6212ff1bad5e83b2023-01-29T12:18:24ZengBMCGenome Medicine1756-994X2023-01-0115111410.1186/s13073-023-01156-9Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populationsJunyi Xin0Mulong Du1Dongying Gu2Kewei Jiang3Mengyun Wang4Mingjuan Jin5Yeting Hu6Shuai Ben7Silu Chen8Wei Shao9Shuwei Li10Haiyan Chu11Linjun Zhu12Chen Li13Kun Chen14Kefeng Ding15Zhengdong Zhang16Hongbing Shen17Meilin Wang18Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Oncology, Nanjing First Hospital, Nanjing Medical UniversityDepartment of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s HospitalCancer Institute, Fudan University Shanghai Cancer CenterDepartment of Epidemiology and Biostatistics at School of Public Health, Zhejiang University School of MedicineDepartment of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, HangzhouDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s HospitalDepartment of Epidemiology and Biostatistics at School of Public Health, Zhejiang University School of MedicineDepartment of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, HangzhouDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning DistrictAbstract Background The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. Methods A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. Results In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (P trend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. Conclusions In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.https://doi.org/10.1186/s13073-023-01156-9Colorectal cancerEast AsianEuropeanPolygenic risk scoreLifestyle |
| spellingShingle | Junyi Xin Mulong Du Dongying Gu Kewei Jiang Mengyun Wang Mingjuan Jin Yeting Hu Shuai Ben Silu Chen Wei Shao Shuwei Li Haiyan Chu Linjun Zhu Chen Li Kun Chen Kefeng Ding Zhengdong Zhang Hongbing Shen Meilin Wang Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations Genome Medicine Colorectal cancer East Asian European Polygenic risk score Lifestyle |
| title | Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations |
| title_full | Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations |
| title_fullStr | Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations |
| title_full_unstemmed | Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations |
| title_short | Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations |
| title_sort | risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure a large scale association study of east asian and european populations |
| topic | Colorectal cancer East Asian European Polygenic risk score Lifestyle |
| url | https://doi.org/10.1186/s13073-023-01156-9 |
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