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

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

doi:10.1038/s41416-021-01655-9

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background
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 geneticpredisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and treestructured 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.

Results
Eight 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.

Conclusions
We show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease.

Original language	English
Journal	British Journal of Cancer
Early online date	15 Dec 2021
DOIs	https://doi.org/10.1038/s41416-021-01655-9
Publication status	E-pub ahead of print - 15 Dec 2021

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Cite this

@article{167b72806c8c44dc8c740fdb458db3d3,

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

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 geneticpredisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and treestructured 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.",

author = "Xiaomeng Zhang and Xue Li and Yazhou He and Phillip Law and Farrington, {Susan M} and Harry Campbell and Tomlinson, {Ian P.M.} and Houlston, {Richard S} and Dunlop, {Malcolm G} and Maria Timofeeva and Evropi Theodoratou",

year = "2021",

month = dec,

day = "15",

doi = "10.1038/s41416-021-01655-9",

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

}

Phenome-wide association study (PheWAS) of colorectal cancer risk SNP effects on health outcomes in UK Biobank. / Zhang, Xiaomeng; Li, Xue ; He, Yazhou; Law, Phillip; Farrington, Susan M ; Campbell, Harry ; Tomlinson, Ian P.M.; Houlston, Richard S; Dunlop, Malcolm G ; Timofeeva, Maria ; Theodoratou, Evropi.

In: British Journal of Cancer, 15.12.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Phenome-wide association study (PheWAS) of colorectal cancer risk SNP effects on health outcomes in UK Biobank

AU - Zhang, Xiaomeng

AU - Li, Xue

AU - He, Yazhou

AU - Law, Phillip

AU - Farrington, Susan M

AU - Campbell, Harry

AU - Tomlinson, Ian P.M.

AU - Houlston, Richard S

AU - Dunlop, Malcolm G

AU - Timofeeva, Maria

AU - Theodoratou, Evropi

PY - 2021/12/15

Y1 - 2021/12/15

N2 - 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 geneticpredisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and treestructured 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.

AB - 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 geneticpredisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and treestructured 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.

U2 - 10.1038/s41416-021-01655-9

DO - 10.1038/s41416-021-01655-9

M3 - Article

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -

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

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