Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

Yufei Wang, James D. McKay, Thorunn Rafnar, Zhaoming Wang, Maria N. Timofeeva, Peter Broderick, Xuchen Zong, Marina Laplana, Yongyue Wei, Younghun Han, Amy Lloyd, Manon Delahaye-Sourdeix, Daniel Chubb, Valerie Gaborieau, William Wheeler, Nilanjan Chatterjee, Gudmar Thorleifsson, Patrick Sulem, Geoffrey Liu, Rudolf KaaksMarc Henrion, Ben Kinnersley, Maxime Vallée, Florence Lecalvez-Kelm, Victoria L. Stevens, Susan M. Gapstur, Wei V. Chen, David Zaridze, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Hans E. Krokan, Maiken Elvestad Gabrielsen, Frank Skorpen, Lars Vatten, Inger Njølstad, Chu Chen, Gary Goodman, Simone Benhamou, Tonu Vooder, Kristjan Välk, Mari Nelis, Andres Metspalu, Marcin Lener, Jan Lubiński, Mattias Johansson, Paolo Vineis, Antonio Agudo, Francoise Clavel-Chapelon, H. Bas Bueno-De-Mesquita, Dimitrios Trichopoulos, Kay Tee Khaw, Mikael Johansson, Elisabete Weiderpass, Anne Tjønneland, Elio Riboli, Mark Lathrop, Ghislaine Scelo, Demetrius Albanes, Neil E. Caporaso, Yuanqing Ye, Jian Gu, Xifeng Wu, Margaret R. Spitz, Hendrik Dienemann, Albert Rosenberger, Li Su, Athena Matakidou, Timothy Eisen, Kari Stefansson, Angela Risch, Stephen J. Chanock, David C. Christiani, Rayjean J. Hung, Paul Brennan, Maria Teresa Landi, Richard S. Houlston, Christopher I. Amos

Research output: Contribution to journalArticlepeer-review

Abstract

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10 â ̂'20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10 â ̂'13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10 â ̂'10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.

Original languageEnglish (US)
Pages (from-to)736-741
Number of pages6
JournalNature genetics
Volume46
Issue number7
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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