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Transcriptome‐wide association study reveals candidate causal genes for lung cancer
Author(s) -
Bossé Yohan,
Li Zhonglin,
Xia Jun,
Manem Venkata,
CarrerasTorres Robert,
Gabriel Aurélie,
Gaudreault Nathalie,
Albanes Demetrius,
Aldrich Melinda C.,
Andrew Angeline,
Arnold Susanne,
Bickeböller Heike,
Bojesen Stig E.,
Brennan Paul,
Brunnstrom Hans,
Caporaso Neil,
Chen Chu,
Christiani David C.,
Field John K.,
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 HErich,
Woll Penella,
Zienolddiny Shan,
Obeidat Ma'en,
Timens Wim,
Hung Rayjean J.,
Joubert Philippe,
Amos Christopher I.,
McKay James D.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32771
Subject(s) - lung cancer , biology , genome wide association study , adenocarcinoma , candidate gene , expression quantitative trait loci , locus (genetics) , transcriptome , carcinogenesis , cancer , genotype , genetics , gene , cancer research , gene expression , pathology , medicine , single nucleotide polymorphism
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.