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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Transcriptome-wide association study reveals candidate causal genes for lung cancer

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  • Yohan Bossé
  • Zhonglin Li
  • Jun Xia
  • Venkata Manem
  • Robert Carreras-Torres
  • Aurélie Gabriel
  • Nathalie Gaudreault
  • Demetrius Albanes
  • Melinda C Aldrich
  • Angeline Andrew
  • Susanne Arnold
  • Heike Bickeböller
  • Stig E Bojesen
  • Paul Brennan
  • Hans Brunnstrom
  • Neil Caporaso
  • Chu Chen
  • David C Christiani
  • John K Field
  • Gary Goodman
  • Kjell Grankvist
  • Richard Houlston
  • Mattias Johansson
  • Mikael Johansson
  • Lambertus A Kiemeney
  • Stephen Lam
  • Maria T Landi
  • Philip Lazarus
  • Loic Le Marchand
  • Geoffrey Liu
  • Olle Melander
  • Gadi Rennert
  • Angela Risch
  • Susan M Rosenberg
  • Matthew B Schabath
  • Sanjay Shete
  • Zhuoyi Song
  • Victoria L Stevens
  • Adonina Tardon
  • H-Erich Wichmann
  • Penella Woll
  • Shan Zienolddiny
  • Ma'en Obeidat
  • Wim Timens
  • Rayjean J Hung
  • Philippe Joubert
  • Christopher I Amos
  • James D McKay
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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.

Original languageEnglish
JournalInternational Journal of Cancer
Volume146
Issue number7
Pages (from-to)1862-1878
Number of pages17
ISSN0020-7136
DOIs
Publication statusPublished - 1 Apr 2020

ID: 59351170