Phenome-wide association study (PheWAS) of colorectal cancer risk SNP effects on health outcomes in UK Biobank

Xiaomeng Zhang,Evropi Theodoratou,Yazhou He,Philip J Law,Xue Li,Richard S Houlston,Maria Timofeeva,Susan M Farrington,Ian P M Tomlinson,Harry Campbell,Malcolm G Dunlop

doi:10.1038/s41416-021-01655-9

Abstract

BackgroundAssociations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies.MethodsWe set out to determine whether genetic predisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. We generated a polygenic risk score (PRS) from CRC genome-wide association studies as a measure of CRC risk. We performed sensitivity analyses to test the robustness of the results and searched the Danish Disease Trajectory Browser (DTB) to replicate the observed associations.ResultsEight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. The PheWAS detected associations were from neoplasms and digestive system disease group (e.g. benign neoplasm of colon, anal and rectal polyp and diverticular disease). The results from the TreeWAS corroborated the results from the PheWAS. These results were replicated in the observational data within the DTB.ConclusionsWe show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer deaths globally [1]
The Disease Trajectory Browser (DTB) suggested diverticular disease happens before colorectal cancer (CRC) and we reported a significant association between CRC predisposition polymorphisms and diverticular disease
We found that an increased CRC polygenic risk score (PRS) was associated with an increased risk of diverticular disease, whereas the DTB suggested diverticular disease happens before CRC

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer deaths globally [1]. Inflammatory bowel disease is among the diseases that are reported to be associated with a higher risk of CRC [3]. Associations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies. METHODS: We set out to determine whether genetic predisposition to CRC is associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. RESULTS: Eight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. CONCLUSIONS: We show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. CRC genetic predisposition is associated with diverticular disease

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