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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Abstract

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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Figure 1: Manhattan plots of lung cancer risk overall and by histological subtype.
Figure 2: Scatterplots of the 6q27, 15q21.1, 8p12 and 11q23.3 susceptibility loci and their association with lung cancer and lung cis-eQTLs.
Figure 3: eQTL and smoking behavior analysis of the 8p21 lung cancer susceptibility locus.

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Acknowledgements

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.

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Drafting of the manuscript: J.D.M., R.J.H., C.I.A. Project coordination: C.I.A., J.D.M., R.J.H., D.C.C., N.E.C., S.C., P. Brennan, M.T.L. Statistical analysis: C.I.A., J.D.M., R.J.H., Y.H., X.Z., R.C.T., X. Ji, X.X., Y.L., J. Byun, K.A.P., D.C.Q., M.N.T., Y. Brhane, D. Zhu. eQTL analysis of candidate variants: J.D.M., Y. Bossé, R.C.T., M.T.L., B.Z., L. Su, M.T.L., M.L. Genomic annotation of candidate variants: D.C.Q., G.C.T., J. Beesley, R.F.T. Assessment of the impact of candidate variants on nicotine addiction: J.D.M., T.R., T.E.T., G.W.R., K.S., D.B.H., L.J.B., R.J.H., SPIRO, L.K., N.C.G., S.M.L., F.G., E.O.J. Assessment of the impact of candidate variants on telomere length: J.D.M., R.J.H., K.A.P., A.D., L.K. Assessment of the impact of candidate variants on lung function: M.D. Tobin, M.S.A., L.V.W., L.K. Sample collection and development of the epidemiological studies: R.J.H., T.R., T.E.T., G.W.R., D.C.C., N.E.C., M.J., G.L., S.E.B., X.W., L.L.M., D.A., H. Bickeböller, M.C.A., W.S.B., A. Tardon, G.R., M.D.T., J.K.F., L.A.K., P.L., A.H., S. Lam, M.B.S., A.S.A., H.S., Y.C.H., J.M.Y., P.A.B., A.C.P., Y.Y., N.D., L. Su, R.Z., Y. Bossé, N.L., J.S.J., A. Mellemgaard, W.S., C.A.H., L.R.W., A.F.-S., G.F.-T., H.F.M.v.d.H., J.H.K., J.D., Z.H., M.P.A.D., M.W.M., H. Brunnström, J. Manjer, O.M., D.C.M., K.O., A. Trichopoulou, R.T., J.A.D., M.P.B., C.C., G.E.G., A.C., F.T., P.W., I.B., H.-E.W., J. Manz, T.R.M., A. Risch, A. Rosenberger, K.G., M.J., F.A.S., M.-S.T., S.M.A., E.B.H., C.B., I.H., V.J., M.K., J.L., A. Mukeria, S.O., T.M.O., G.S., B.S., D. Zaridze, P. Bakke, V.S., S.Z., E.J.D., L.M.B., W.-P.K., Y.-T.G., R.S.H., J. McLaughlin, V.L.S., P.J., M.L., D.C.N., M.O., W.T., L. Song, M.S.A., M.D. Teare, M.R.S., A.K., C.P., R.J.H., J.D.M., M.T.L. Genetic sharing analysis: R.C.T., S. Lindströem, X. Jiang, J.D.M., R.J.H.

Corresponding author

Correspondence to Christopher I Amos.

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Competing interests

T.R., T.E.T., G.W.R. and K.S. are employees of the biotechnology company deCODE Genetics, a subsidiary of Amgen.

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A list of members appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1, 3–6, 8 and 9, and Supplementary Note. (PDF 8760 kb)

Supplementary Table 2

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)

Supplementary Table 7

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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