Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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Ferlay, J. et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11 (International Agency for Research on Cancer, 2013).
Mucci, L.A. et al. Familial risk and heritability of cancer among twins in Nordic countries. J. Am. Med. Assoc. 315, 68–76 (2016).
Timofeeva, M.N. et al. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Hum. Mol. Genet. 21, 4980–4995 (2012).
Wang, Y. et al. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat. Genet. 46, 736–741 (2014).
Amos, C.I. et al. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers. Cancer Epidemiol. Biomarkers Prev. 26, 126–135 (2017).
Wang, Y. et al. Deciphering associations for lung cancer risk through imputation and analysis of 12,316 cases and 16,831 controls. Eur. J. Hum. Genet. 23, 1723–1728 (2015).
Durham, A.L. & Adcock, I.M. The relationship between COPD and lung cancer. Lung Cancer 90, 121–127 (2015).
Yuan, H. et al. A novel genetic variant in long non-coding RNA gene NEXN-AS1 is associated with risk of lung cancer. Sci. Rep. 6, 34234 (2016).
Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).
Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).
Jostins, L. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
McGovern, D.P. et al. Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. Hum. Mol. Genet. 19, 3468–3476 (2010).
Yang, S.K. et al. Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 63, 80–87 (2014).
Brenner, D.R. et al. Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls. Hum. Genet. 132, 579–589 (2013).
Moulton, E.A., Elman, I., Becerra, L.R., Goldstein, R.Z. & Borsook, D. The cerebellum and addiction: insights gained from neuroimaging research. Addict. Biol. 19, 317–331 (2014).
Yu, C.T. et al. The novel protein suppressed in lung cancer down-regulated in lung cancer tissues retards cell proliferation and inhibits the oncokinase Aurora-A. J. Thorac. Oncol. 6, 988–997 (2011).
Fernandez-Cuesta, L. et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov. 4, 415–422 (2014).
Lan, Q. et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat. Genet. 44, 1330–1335 (2012).
Landi, M.T. et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am. J. Hum. Genet. 85, 679–691 (2009).
Truong, T. et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J. Natl. Cancer Inst. 102, 959–971 (2010).
Walsh, K.M. et al. Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nat. Genet. 46, 731–735 (2014).
Codd, V. et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet. 45, 422–427 (2013).
Zhang, C. et al. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Hum. Mol. Genet. 24, 5356–5366 (2015).
Walsh, K.M. et al. Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk. Oncotarget 6, 42468–42477 (2015).
Fehringer, G. et al. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations. Cancer Res. 76, 5103–5114 (2016).
Amundadottir, L.T. et al. Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family. PLoS Med. 1, e65 (2004).
Lindelöf, B. & Eklund, G. Analysis of hereditary component of cancer by use of a familial index by site. Lancet 358, 1696–1698 (2001).
Li, Y. et al. FastPop: a rapid principal component derived method to infer intercontinental ancestry using genetic data. BMC Bioinformatics 17, 122 (2016).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Viechtbauer, W. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36, 1–48 (2010).
Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
Li, J. & Ji, L. Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95, 221–227 (2005).
Wakefield, J. A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am. J. Hum. Genet. 81, 208–227 (2007).
Hao, K. et al. Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genet. 8, e1003029 (2012).
Shi, J. et al. Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue. Nat. Commun. 27, 3365 (2014).
GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
Soler Artigas, M. et al. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation. Nat. Commun. 6, 8658 (2015).
Pooley, K.A. et al. Telomere length in prospective and retrospective cancer case–control studies. Cancer Res. 70, 3170–3176 (2010).
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
Bulik-Sullivan, B.K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).
Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441–447 (2010).
Hemminki, K. & Bermejo, J.L. Relationships between familial risks of cancer and the effects of heritable genes and their SNP variants. Mutat. Res. 592, 6–17 (2005).
Bahcall, O.G. iCOGS collection provides a collaborative model. Nat. Genet. 45, 343 (2013).
Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by grants U19-CA148127 and CA148127S1. ILCCO data harmonization is supported by the Cancer Care Ontario Research Chair of Population Studies to R.J.H. and the Lunenfeld-Tanenbaum Research Institute, Sinai Health System. Additional funding information is provided in the Supplementary Note.
The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1).
IARC acknowledges and thanks V. Gaborieau, M. Foll, L. Fernandez-Cuesta, P. Chopard, T. Delhomme and A. Chabrier for their technical assistance in this project.
The authors would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL data set at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, the Respiratory Health Network of the FRQS and the Canadian Institutes of Health Research (MOP-123369). Y. Bossé holds a Canada Research Chair in Genomics of Heart and Lung Diseases.
T.R., T.E.T., G.W.R. and K.S. are employees of the biotechnology company deCODE Genetics, a subsidiary of Amgen.
A list of members appears in the Supplementary Note.
Supplementary Figures 1–8, Supplementary Tables 1, 3–6, 8 and 9, and Supplementary Note. (PDF 8760 kb)
Results from analysis for SNPs with P <1 × 10–5 for overall lung cancer and subsets defined by histology and smoking status. (XLSX 3937 kb)
Genomic annotations of loci containing sentinel variants. (XLSX 138 kb)
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McKay, J., Hung, R., Han, Y. et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat Genet 49, 1126–1132 (2017). https://doi.org/10.1038/ng.3892
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