| Title: | Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer |
| Journal: | Human Genomics |
| Published: | 9 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40635049/ |
| DOI: | https://doi.org/10.1186/s40246-025-00791-0 |
| URL: | https://humgenomics.biomedcentral.com/counter/pdf/10.1186/s40246-025-00791-0 |
Publication 16588
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Abstract
BackgroundMany 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.MethodsWe 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.ResultsWe 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.ConclusionsAs 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.</p>
15 Keywords
- Aged
- Colorectal Neoplasms
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Phenomics
- Phenotype
- Polymorphism, Single Nucleotide
- Risk Factors
- United Kingdom
17 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 47377 | Improved Polygenic Risk Score Calculation and Sub-classification of Disease by the Incorporation of Functional Data. |
Enabling scientific discoveries that improve human health