Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
|State||Published - Dec 1 2018|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health (NIH) for the research of lung cancer (grants P30CA023108, P20GM103534, and R01LM012012); Transdisciplinary Research in Cancer of the Lung (TRICL) (grant U19CA148127); UICC American Cancer Society Beginning Investigators Fellowship funded by the Union for International Cancer Control (UICC) (to X.J.). CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN.CARET study was supported by NIH awards UM1 CA167462, UO1-CA6367307, CA111703, and R01 CA151989. The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by NIH grants CA092824, CA090578, and CA074386. The Multiethnic Cohort Study was partially supported by NIH grants CA164973, CA033619, CA63464, and CA148127. The MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. R.T is supported by a Canada Research Chair in Pharmacoge-nomics, CIHR grant (FDN-154294), and CAMH. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study was supported by NIH R01 CA144034 and UM1 CA182876. The Singapore Chinese Health Study (SCHS) was supported by NIH R01 CA144034 and UM1 CA182876. The TLC study has been supported in part by the James & Esther King Biomedical Research Program (09KN-15), NIH grant P50 CA119997 and P30CA76292. The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH, K07CA172294 and U01HG004798. The Copenhagen General Population Study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study was supported by NIH grant P20RR018787. The MDACC study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568), Cancer Prevention & Research Institute of Texas (RP130502), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. It is also supported by NIH grant UL1TR000117 and P30 CA177558 using Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre, and Weston Park Hospital Cancer Charity. F.T. was supported by a clinical PhD fellowship funded by the Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre. The authors at Laval would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL dataset at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l’Institut universitaire de cardiologie et de pneu-mologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP-123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The research undertaken by M.T., L.W., and M.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313).
© 2018, The Author(s).
ASJC Scopus subject areas
- Physics and Astronomy (all)
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)