Bossé, Y., Li, Z., Xia, J. et al. (45 more authors) (2020) Transcriptome‐wide association study reveals candidate causal genes for lung cancer. International Journal of Cancer, 146 (7). pp. 1862-1878. ISSN 0020-7136
Abstract
We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. We performed transcriptome‐wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma, small cell lung cancer) and smoking subgroups (never‐ and ever‐smokers). We performed replication analysis using lung data from the Genotype‐Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever‐smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (PTWAS=1.09E‐99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (PTWAS=3.72E‐6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3‐adenocarcinoma on 9p13.3 was replicated using GTEx (PTWAS=6.55E‐5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influence lung cancer risk.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 UICC. This is an author-produced version of a paper subsequently published in International Journal of Cancer. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Lung cancer; transcriptome‐wide association study; GWAS; lung eQTL |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Funding Information: | Funder Grant number WESTON PARK HOSPITAL CANCER CHARITY CA115 CANCER RESEARCH UK (CRUK) C5410/A7315. CANCER RESEARCH UK C5410/A7315. SHEFFIELD HOSPITALS CHARITABLE TRUST 091002 CANCER RESEARCH UK C5410/A7315. SHEFFIELD HOSPITALS CHARITABLE TRUST (SPECIAL TRUSTEES) 091002 SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST ECMC |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 11 Nov 2019 16:44 |
Last Modified: | 16 Dec 2021 17:12 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/ijc.32771 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:153348 |