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

Bossé, Yohan ; Li, Zhonglin ; Xia, Jun ; Manem, Venkata ; Carreras-Torres, Robert ; Gabriel, Aurélie ; Gaudreault, Nathalie ; Albanes, Demetrius ; Aldrich, Melinda C. and Andrew, Angeline , et al. (2020) In International Journal of Cancer 146(7). p.1862-1878
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... (More)

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.

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published
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keywords
GWAS, lung cancer, lung eQTL, transcriptome-wide association study
in
International Journal of Cancer
volume
146
issue
7
pages
17 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85076520927
  • pmid:31696517
ISSN
0020-7136
DOI
10.1002/ijc.32771
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English
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yes
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be4adfa3-d184-4211-b54f-78bbcd74c605
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2020-01-07 17:50:21
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2020-02-11 13:16:45
@article{be4adfa3-d184-4211-b54f-78bbcd74c605,
  abstract     = {<p>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<sub>TWAS</sub> = 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<sub>TWAS</sub> = 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<sub>TWAS</sub> = 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.</p>},
  author       = {Bossé, Yohan and Li, Zhonglin and Xia, Jun and Manem, Venkata and Carreras-Torres, Robert and Gabriel, Aurélie and Gaudreault, Nathalie and Albanes, Demetrius and Aldrich, Melinda C. and Andrew, Angeline and Arnold, Susanne and Bickeböller, Heike and Bojesen, Stig E. and Brennan, Paul and Brunnstrom, Hans and Caporaso, Neil and Chen, Chu and Christiani, David C. and Field, John K. and Goodman, Gary and Grankvist, Kjell and Houlston, Richard and Johansson, Mattias and Johansson, Mikael and Kiemeney, Lambertus A. and Lam, Stephen and Landi, Maria T. and Lazarus, Philip and Le Marchand, Loic and Liu, Geoffrey and Melander, Olle and Rennert, Gadi and Risch, Angela and Rosenberg, Susan M. and Schabath, Matthew B. and Shete, Sanjay and Song, Zhuoyi and Stevens, Victoria L. and Tardon, Adonina and Wichmann, H. Erich and Woll, Penella and Zienolddiny, Shan and Obeidat, Ma'en and Timens, Wim and Hung, Rayjean J. and Joubert, Philippe and Amos, Christopher I. and McKay, James D.},
  issn         = {0020-7136},
  language     = {eng},
  month        = {04},
  number       = {7},
  pages        = {1862--1878},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  title        = {Transcriptome-wide association study reveals candidate causal genes for lung cancer},
  url          = {http://dx.doi.org/10.1002/ijc.32771},
  doi          = {10.1002/ijc.32771},
  volume       = {146},
  year         = {2020},
}