Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.
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This research was supported by funding from the National Institutes of Health (US NCI R25T CA112355 and R01 CA201358; PI: Witte) and the Canadian Institute for Health Research (Foundation grant FDN 167273, PI: Hung; Canada Research Chair, PI: Hung). The OncoArray project was supported by NIH U19 CA203654 (MPI: Hung, Amos, Brennan, Lin). The Boston Lung Cancer Study was funded by NIH (NCI) U01CA209414 (PI: Christiani). The lung eQTL study at Laval University was supported by the Fondation de l’Institut universitaire de cardiologie et de pneumologie de Québec and the Canadian Institutes of Health Research (MOP − 123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The EAGLE study was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. The Multiethnic Cohort Study is supported by National Institutes of Health (CA164973). The CARET study was supported by the National Institutes of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), U01 CA6367307 (PIs: Omen, Goodman); R01 CA111703 (PI: Chen), 5R01 CA151989-01A1 (PI: Doherty) and U01 CA167462 (PI: Chen). M.B.S. was supported in part by a Cancer Center Support Grant (P30 CA076292) and by NIH P50 CA119997. R.M.M. is supported by a CRUK programme grant, the Integrative Cancer Epidemiology Programme (C18281/A19169), and by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol.
Dr Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. M.P.D. is supported by the Roy Castle Lung Cancer Foundation UK.
The datasets generated during and/or analyzed during the current study are available from the authors on request. Genotype data for the Oncoarray Consortium Lung Cancer studies have been deposited in the database of Genotypes and Phenotypes (dbGaP) under accession: phs001273.v2.p2. Readers interested in obtaining a copy of the lung cancer GWAS summary statistics can do so by completing the proposal request form at http://oncoarray.dartmouth.edu/. The UK Biobank in an open access resource, available at https://www.ukbiobank.ac.uk/researchers/.
All data supporting the findings of this study are available within the article and its supplementary information files, and from the corresponding authors upon reasonable request. A reporting summary for this article is available as a Supplementary file.
Supplementary information is available for this paper at https://doi.org/10.1038/s41467-019-13855-2.
Kachuri, Linda; Johansson, Mattias; Rashkin, Sara R.; Graff, Rebecca E.; Bossé, Yohan; Manem, Venkata; Caporaso, Neil E.; Landi, Maria Teresa; Christiani, David C.; Vineis, Paolo; Liu, Geoffrey; Scelo, Ghislaine; Zaridze, David; Shete, Sanjay S; Albanes, Demetrius; Aldrich, Melinda C.; Tardón, Adonina; Rennert, Gad; Chen, Chu; Goodman, Gary E.; Doherty, Jennifer A.; Bickeböller, Heike; Field, John K.; Davies, Michael P; Teare, M. Dawn; Kiemeney, Lambertus A.; Bojesen, Stig E.; Haugen, Aage; Zienolddiny, Shanbeh; Lam, Stephen; Le Marchand, Loïc; Cheng, Iona; Schabath, Matthew B.; Duell, Eric J.; Andrew, Angeline S.; Manjer, Jonas; Lazarus, Philip; Arnold, Susanne M.; McKay, James D.; Emami, Nima C.; Warkentin, Matthew T.; Brhane, Yonathan; Obeidat, Ma'en; Martin, Richard M.; Relton, Caroline; Davey Smith, George; Haycock, Philip C.; Amos, Christopher I.; Brennan, Paul; Witte, John S.; and Hung, Rayjean J., "Immune-Mediated Genetic Pathways Resulting in Pulmonary Function Impairment Increase Lung Cancer Susceptibility" (2020). Markey Cancer Center Faculty Publications. 147.
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