Transcriptome-wide association study reveals candidate causal genes for lung cancer
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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.; 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, H. Erich; Woll, Penella; Zienolddiny, Shan; Obeidat, Ma'en; Timens, Wim; Hung, Rayjean J.; Joubert, Philippe; Amos, Christopher I.; McKay, James D.
In: International Journal of Cancer, Vol. 146, No. 7, 04.2020, p. 1862-1878.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Transcriptome-wide association study reveals candidate causal genes for lung cancer
AU - Bossé, Yohan
AU - Li, Zhonglin
AU - Xia, Jun
AU - Manem, Venkata
AU - Carreras-Torres, Robert
AU - Gabriel, Aurélie
AU - Gaudreault, Nathalie
AU - Albanes, Demetrius
AU - Aldrich, Melinda C.
AU - Andrew, Angeline
AU - Arnold, Susanne
AU - Bickeböller, Heike
AU - Bojesen, Stig E.
AU - Brennan, Paul
AU - Brunnstrom, Hans
AU - Caporaso, Neil
AU - Chen, Chu
AU - Christiani, David C.
AU - Field, John K.
AU - Goodman, Gary
AU - Grankvist, Kjell
AU - Houlston, Richard
AU - Johansson, Mattias
AU - Johansson, Mikael
AU - Kiemeney, Lambertus A.
AU - Lam, Stephen
AU - Landi, Maria T.
AU - Lazarus, Philip
AU - Le Marchand, Loic
AU - Liu, Geoffrey
AU - Melander, Olle
AU - Rennert, Gadi
AU - Risch, Angela
AU - Rosenberg, Susan M.
AU - Schabath, Matthew B.
AU - Shete, Sanjay
AU - Song, Zhuoyi
AU - Stevens, Victoria L.
AU - Tardon, Adonina
AU - Wichmann, H. Erich
AU - Woll, Penella
AU - Zienolddiny, Shan
AU - Obeidat, Ma'en
AU - Timens, Wim
AU - Hung, Rayjean J.
AU - Joubert, Philippe
AU - Amos, Christopher I.
AU - McKay, James D.
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - GWAS
KW - lung cancer
KW - lung eQTL
KW - transcriptome-wide association study
UR - http://www.scopus.com/inward/record.url?scp=85076520927&partnerID=8YFLogxK
U2 - 10.1002/ijc.32771
DO - 10.1002/ijc.32771
M3 - Journal article
C2 - 31696517
AN - SCOPUS:85076520927
VL - 146
SP - 1862
EP - 1878
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 7
ER -
ID: 249431330