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

Bosse, Yohan (author)
Laval University,Institut universitaire de cardiologie et de pneumologie de Québec
Li, Zhonglin (author)
Institut universitaire de cardiologie et de pneumologie de Québec,Laval University
Xia, Jun (author)
Baylor College of Medicine
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Manem, Venkata (author)
Laval University,Institut universitaire de cardiologie et de pneumologie de Québec
Carreras-Torres, Robert (author)
International Agency for Research on Cancer, World Health Organization
Gabriel, Aurelie (author)
International Agency for Research on Cancer, World Health Organization
Gaudreault, Nathalie (author)
Institut universitaire de cardiologie et de pneumologie de Québec,Laval University
Albanes, Demetrius (author)
National Cancer Institute, NCI
Aldrich, Melinda C. (author)
Vanderbilt University Medical Center,Fred Hutchinson Cancer Research Center
Andrew, Angeline (author)
Dartmouth-Hitchcock Medical Center,Radboud University Medical Center
Arnold, Susanne (author)
University of Kentucky
Bickeboeller, Heike (author)
University Medical Center Göttingen
Bojesen, Stig E. (author)
Copenhagen University Hospital
Brennan, Paul (author)
International Agency for Research on Cancer, World Health Organization
Brunnstrom, Hans (author)
Lund University,Lunds universitet,Förbättrad diagnostik och prognostik vid lungcancer och metastaser till lunga,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Improved diagnostics and prognostics of lung cancer and metastases to the lungs,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
Caporaso, Neil (author)
National Cancer Institute, NCI
Chen, Chu (author)
Harvard University
Christiani, David C. (author)
Field, John K. (author)
University of Liverpool
Goodman, Gary (author)
Swedish Medical Center
Grankvist, Kjell (author)
Umeå University,Umeå universitet,Klinisk kemi
Houlston, Richard (author)
Institute of Cancer Research London
Johansson, Mattias (author)
International Agency for Research on Cancer, World Health Organization
Johansson, Mikael (author)
Umeå University,Umeå universitet,Onkologi
Kiemeney, Lambertus A. (author)
Lam, Stephen (author)
British Columbia Cancer Agency
Landi, Maria T. (author)
National Cancer Institute, NCI
Lazarus, Philip (author)
Washington State University
Le Marchand, Loic (author)
University of Hawaii Cancer Center
Liu, Geoffrey (author)
Princess Margaret Hospital University of Toronto
Melander, Olle (author)
Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups
Rennert, Gadi (author)
Carmel Medical Center
Risch, Angela (author)
University of Salzburg
Rosenberg, Susan M. (author)
Baylor College of Medicine
Schabath, Matthew B. (author)
H. Lee Moffitt Cancer Center & Research Institute
Shete, Sanjay (author)
University of Texas
Song, Zhuoyi (author)
Baylor College of Medicine
Stevens, Victoria L. (author)
American Cancer Society
Tardon, Adonina (author)
University of Oviedo
Wichmann, H-Erich (author)
Helmholtz Zentrum München
Woll, Penella (author)
University of Sheffield
Zienolddiny, Shan (author)
National Institute of Occupational Health, Norway
Obeidat, Ma'en (author)
University of British Columbia,St. Paul’s Hospital
Timens, Wim (author)
University Medical Center Groningen
Hung, Rayjean J. (author)
Sinai Health System
Joubert, Philippe (author)
Laval University,Institut universitaire de cardiologie et de pneumologie de Québec
Amos, Christopher I. (author)
Baylor College of Medicine
McKay, James D. (author)
International Agency for Research on Cancer, World Health Organization
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 (creator_code:org_t)
2019-12-09
2020
English.
In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:7, s. 1862-1878
Related links:
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http://dx.doi.org/10...
https://urn.kb.se/re...
https://doi.org/10.1...
https://lup.lub.lu.s...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Keyword

lung cancer
transcriptome-wide association study
GWAS
lung eQTL
GWAS
lung cancer
lung eQTL
transcriptome-wide association study

Publication and Content Type

ref (subject category)
art (subject category)

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