Transcriptome-wide association study reveals candidate causal genes for lung cancer

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Bosse, Yohan, Li, Zhonglin, Xia, Jun, Manem, Venkata, Carreras-Torres, Robert, Gabriel, Aurelie, Gaudreault, Nathalie, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline et al (show 38 more authors) , Arnold, Susanne, Bickeboeller, Heike, Bojesen, Stig E, Brennan, Paul, Brunnstrom, Hans, Caporaso, Neil, Chen, Chu, Christiani, David C, Field, John K ORCID: 0000-0003-3951-6365, Goodman, Gary, Grankvist, Kjell, Houlston, Richard, Johansson, Mattias, Johansson, Mikael, Kiemeney, Lambertus A, Lam, Stephen, Landi, Maria T, Lazarus, Philip, Le Marchand, Loic, Liu, Geoffrey, Melander, Olle, Rennert, Gadi, Risch, Angela, Rosenberg, Susan M, Schabath, Matthew B, Shete, Sanjay, Song, Zhuoyi, Stevens, Victoria L, Tardon, Adonina, Wichmann, H-Erich, Woll, Penella, Zienolddiny, Shan, Obeidat, Ma'en, Timens, Wim, Hung, Rayjean J, Joubert, Philippe, Amos, Christopher I and McKay, James D (2020) Transcriptome-wide association study reveals candidate causal genes for lung cancer. INTERNATIONAL JOURNAL OF CANCER, 146 (7). pp. 1862-1878.

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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 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 (p_TWAS = 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 (p_TWAS = 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 (p_TWAS = 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.

Item Type:	Article
Uncontrolled Keywords:	lung cancer, transcriptome-wide association study, GWAS, lung eQTL
Depositing User:	Symplectic Admin
Date Deposited:	08 Nov 2019 09:20
Last Modified:	19 Jan 2023 00:20
DOI:	10.1002/ijc.32771
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3060986