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

James D. McKay, Rayjean J. Hung, Younghun Han, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil E. Caporaso, Mattias Johansson, Xiangjun Xiao, Yafang Li, Jinyoung Byun, Alison Dunning, Karen A. Pooley, David C. Qian, Xuemei Ji, Geoffrey Liu, Maria N. Timofeeva, Stig E. Bojesen, Xifeng Wu, Loic Le MarchandDemetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, M. Dawn Teare, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Hongbing Shen, Yun Chul Hong, Jian Min Yuan, Pier Alberto Bertazzi, Angela C. Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher A. Haiman, Lesley M. Butler, SpiroMeta Consortium

Research output: Contribution to journalArticle

104 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1126-1132
Number of pages7
JournalNature Genetics
Volume49
Issue number7
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics

Cite this

McKay, J. D., Hung, R. J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D. C., Caporaso, N. E., Johansson, M., Xiao, X., Li, Y., Byun, J., Dunning, A., Pooley, K. A., Qian, D. C., Ji, X., Liu, G., Timofeeva, M. N., Bojesen, S. E., Wu, X., ... SpiroMeta Consortium (2017). Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nature Genetics, 49(7), 1126-1132. https://doi.org/10.1038/ng.3892