Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer
Abstract Background Many factors, including environmental and genetic variables, contribute to Colorectal Cancer (CRC) risk. The genetic components of risk can be divided into monogenic and polygenic factors. Just as monogenic factors can increase risk for more than one condition, polygenic factors...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
|
| Series: | Human Genomics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40246-025-00791-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849235126099116032 |
|---|---|
| author | Elisabeth A. Rosenthal Wei-Qi Wei Yuan Luo Bahram Namjou-Khales Daniel J. Schaid Edward D. Esplin Michael Lape Leah Kottyan Jennifer Allen Pacheco Chunhua Weng Adam Samuel Gordon Iftikhar J. Kullo David R. Crosslin William M. Grady Li Hsu Ulrike Peters Gail P. Jarvik |
| author_facet | Elisabeth A. Rosenthal Wei-Qi Wei Yuan Luo Bahram Namjou-Khales Daniel J. Schaid Edward D. Esplin Michael Lape Leah Kottyan Jennifer Allen Pacheco Chunhua Weng Adam Samuel Gordon Iftikhar J. Kullo David R. Crosslin William M. Grady Li Hsu Ulrike Peters Gail P. Jarvik |
| author_sort | Elisabeth A. Rosenthal |
| collection | DOAJ |
| description | Abstract Background Many factors, including environmental and genetic variables, contribute to Colorectal Cancer (CRC) risk. The genetic components of risk can be divided into monogenic and polygenic factors. Just as monogenic factors can increase risk for more than one condition, polygenic factors may also underlie multiple phenotypes, including behavioral traits. In order to understand the biology of CRC risk better, it is important to understand the shared polygenic genetic architecture contributing to CRC risk and other phenotypes, including CRC associated risk factors. Methods We investigated potential shared genetics by performing a Phenome-wide association study (PheWAS) with a multi-ancestry CRC polygenic risk score (PRS). The discovery cohort (N = 426,464) consisted of ancestrally diverse participants from the United Kingdom Biobank. The replication cohort (N = 87,271) consisted of ancestrally diverse participants from the electronic Medical Records and Genomics Network phase 3. We used a mixed-effects model to adjust for the presence of related individuals. To preserve power, we limited the number of tests by restricting analysis to ancestor phecodes derived from the electronic health record (EHR) that were not likely to be a result of CRC or its treatment. Results We discovered and replicated associations between the CRC PRS and breast cancer, prostate cancer, obesity, smoking and alcohol use (discovery p < 1.1e-4; replication p < 0.0019). The association between CRC risk and prostate cancer may be a novel finding, whereas the association with breast cancer has been previously observed using orthogonal methods. The association between CRC risk and behavioral risk factors corroborate previous studies, also using orthogonal methods, and may reveal potential prevention or treatment strategies. Conclusions As these results corroborate findings from other studies using orthogonal methods, we demonstrate that a CRC PRS can be used as a proxy for genetic risk for CRC when investigating shared genetics between CRC and other phenotypes. Further study of the relationship between PRS from multiple traits with EHR data may reveal additional shared genetic factors. Ultimately, understanding these underlying genetic correlations may identify prevention and treatment strategies for CRC. |
| format | Article |
| id | doaj-art-2d7ab6716bcf4bf9be9965d7d3559b6c |
| institution | Kabale University |
| issn | 1479-7364 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Human Genomics |
| spelling | doaj-art-2d7ab6716bcf4bf9be9965d7d3559b6c2025-08-20T04:02:54ZengBMCHuman Genomics1479-73642025-07-011911910.1186/s40246-025-00791-0Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancerElisabeth A. Rosenthal0Wei-Qi Wei1Yuan Luo2Bahram Namjou-Khales3Daniel J. Schaid4Edward D. Esplin5Michael Lape6Leah Kottyan7Jennifer Allen Pacheco8Chunhua Weng9Adam Samuel Gordon10Iftikhar J. Kullo11David R. Crosslin12William M. Grady13Li Hsu14Ulrike Peters15Gail P. Jarvik16Department of Medicine, Division of Medical Genetics, University of Washington Medical CenterDepartment of Biomedical Informatics, Vanderbilt University Medical CenterFeinberg School of Medicine, Northwestern UniversityCenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical CenterDepartment of Quantitative Health Sciences, Mayo ClinicLabcorp GeneticsDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical CenterDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical CenterCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern UniversityDepartment of Biomedical Informatics, ColumbiaCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern UniversityDepartment of Cardiovascular Medicine, Mayo ClinicDivision of Biomedical Informatics and Genomics, School of MedicineTranslational Sciences and Therapeutics Division and Public Health Sciences Division, Fred Hutchinson Cancer CenterPublic Health Sciences Division, Fred Hutchinson Cancer CenterDivision of Gastroenterology, University of Washington School of MedicineDepartment of Medicine, Division of Medical Genetics, University of Washington Medical CenterAbstract Background Many factors, including environmental and genetic variables, contribute to Colorectal Cancer (CRC) risk. The genetic components of risk can be divided into monogenic and polygenic factors. Just as monogenic factors can increase risk for more than one condition, polygenic factors may also underlie multiple phenotypes, including behavioral traits. In order to understand the biology of CRC risk better, it is important to understand the shared polygenic genetic architecture contributing to CRC risk and other phenotypes, including CRC associated risk factors. Methods We investigated potential shared genetics by performing a Phenome-wide association study (PheWAS) with a multi-ancestry CRC polygenic risk score (PRS). The discovery cohort (N = 426,464) consisted of ancestrally diverse participants from the United Kingdom Biobank. The replication cohort (N = 87,271) consisted of ancestrally diverse participants from the electronic Medical Records and Genomics Network phase 3. We used a mixed-effects model to adjust for the presence of related individuals. To preserve power, we limited the number of tests by restricting analysis to ancestor phecodes derived from the electronic health record (EHR) that were not likely to be a result of CRC or its treatment. Results We discovered and replicated associations between the CRC PRS and breast cancer, prostate cancer, obesity, smoking and alcohol use (discovery p < 1.1e-4; replication p < 0.0019). The association between CRC risk and prostate cancer may be a novel finding, whereas the association with breast cancer has been previously observed using orthogonal methods. The association between CRC risk and behavioral risk factors corroborate previous studies, also using orthogonal methods, and may reveal potential prevention or treatment strategies. Conclusions As these results corroborate findings from other studies using orthogonal methods, we demonstrate that a CRC PRS can be used as a proxy for genetic risk for CRC when investigating shared genetics between CRC and other phenotypes. Further study of the relationship between PRS from multiple traits with EHR data may reveal additional shared genetic factors. Ultimately, understanding these underlying genetic correlations may identify prevention and treatment strategies for CRC.https://doi.org/10.1186/s40246-025-00791-0PheWASCross-trait genetic correlationPolygenic riskColorectal cancerUK BiobankeMERGE |
| spellingShingle | Elisabeth A. Rosenthal Wei-Qi Wei Yuan Luo Bahram Namjou-Khales Daniel J. Schaid Edward D. Esplin Michael Lape Leah Kottyan Jennifer Allen Pacheco Chunhua Weng Adam Samuel Gordon Iftikhar J. Kullo David R. Crosslin William M. Grady Li Hsu Ulrike Peters Gail P. Jarvik Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer Human Genomics PheWAS Cross-trait genetic correlation Polygenic risk Colorectal cancer UK Biobank eMERGE |
| title | Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer |
| title_full | Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer |
| title_fullStr | Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer |
| title_full_unstemmed | Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer |
| title_short | Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer |
| title_sort | phenome wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer |
| topic | PheWAS Cross-trait genetic correlation Polygenic risk Colorectal cancer UK Biobank eMERGE |
| url | https://doi.org/10.1186/s40246-025-00791-0 |
| work_keys_str_mv | AT elisabetharosenthal phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT weiqiwei phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT yuanluo phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT bahramnamjoukhales phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT danieljschaid phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT edwarddesplin phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT michaellape phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT leahkottyan phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT jenniferallenpacheco phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT chunhuaweng phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT adamsamuelgordon phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT iftikharjkullo phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT davidrcrosslin phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT williammgrady phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT lihsu phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT ulrikepeters phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer AT gailpjarvik phenomewideassociationstudyidentifiesmultipletraitsassociatedwithapolygenicriskscoreforcolorectalcancer |