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Transcriptome-wide association study reveals candidate causal genes for lung cancer
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our 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 and 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 influences lung cancer risk.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019.
Keywords [en]
lung cancer, transcriptome-wide association study, GWAS, lung eQTL
National Category
Cancer and Oncology Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-166840DOI: 10.1002/ijc.32771ISI: 000501377100001PubMedID: 31696517OAI: oai:DiVA.org:umu-166840DiVA, id: diva2:1382329
Funder
NIH (National Institute of Health), S10-RR024574NIH (National Institute of Health), P30-CA125123NIH (National Institute of Health), P30-AI036211NIH (National Institute of Health), DP1-CA174424NIH (National Institute of Health), R35-GM122598NIH (National Institute of Health), U19 CA203654NIH (National Institute of Health), U19 CA148127NIH (National Institute of Health), U01-CA167462NIH (National Institute of Health), UM1-CA167462NIH (National Institute of Health), U01-CA063673Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02

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Grankvist, KjellJohansson, Mikael

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Bosse, YohanGrankvist, KjellJohansson, Mikael
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Department of Medical BiosciencesDepartment of Radiation Sciences
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International Journal of Cancer
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