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.
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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.).
Due to the large number of funding sources, only the first few are listed in this section. For the complete list of funding sources, please download this article.
The data that support the findings of this study are available. The access numbers are “phs000336.v1.p1.c1” for EAGLE study, “phs000753.v1.p1” for MDACC study, and “phs001273” for Oncoarray study in dbGAP. The IARC study was made available at http://www.ceph.fr/cancer.
Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-05074-y.
Ji, Xuemei; Bossé, Yohan; Landi, Maria Teresa; Gui, Jiang; Xiao, Xiangjun; Qian, David; Joubert, Philippe Joubert; Lamontagne, Maxime; Li, Yafang; Gorlov, Ivan; de Biasi, Mariella; Han, Younghun; Gorlova, Olga; Hung, Rayjean J.; Wu, Xifeng; McKay, James; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil; Johansson, Mattias; Liu, Geoffrey; Bojesen, Stig E.; Marchand, Loic Le; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; and Arnold, Susanne M., "Identification of Susceptibility Pathways for the Role of Chromosome 15q25.1 in Modifying Lung Cancer Risk" (2018). Markey Cancer Center Faculty Publications. 128.
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