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 Kaaks; Marc 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

doi:10.1038/ng.3002

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 journal › Article › peer-review

348 Scopus citations

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 language	English
Pages (from-to)	736-741
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	7
DOIs	https://doi.org/10.1038/ng.3002
State	Published - 2014
Externally published	Yes

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Wang, Y., McKay, J. D., Rafnar, T., Wang, Z., Timofeeva, M. N., Broderick, P., Zong, X., Laplana, M., Wei, Y., Han, Y., Lloyd, A., Delahaye-Sourdeix, M., Chubb, D., Gaborieau, V., Wheeler, W., Chatterjee, N., Thorleifsson, G., Sulem, P., Liu, G., ... Amos, C. I. (2014). Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nature Genetics, 46(7), 736-741. https://doi.org/10.1038/ng.3002

@article{616a0bb3472142f2a6c9202cb1bebd2d,

title = "Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer",

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 {\^a}{\^ }'20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10 {\^a}{\^ }'13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10 {\^a}{\^ }'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.",

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

note = "Funding Information: We thank all individuals who participated in this study. We are also grateful to the patients, clinicians and allied health care professions. We thank Z. Chen and K. Boyle for sample handling and data management of the Toronto study, and L. Admas and L.R. Zhang for field recruitment. We thank L. Su, Y. Zhao, G. Liu, J. Wain, R. Heist and K. Asomaning for providing computing support at MDACC. We thank G. Thomas and Synergy Lyon Cancer (Lyon France) for high performance computing support and J. Olivier and A. Chabrier for IARC{\textquoteright}s PGM ion torrent sequencing optimization and TaqMan genotyping, respectively. We thank D. Goldgar for sharing information from The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) on sequence variation in BRCA2 from familial breast cancer analysis. We acknowledge the Icelandic Cancer Registry (http://www. krabbameinsskra.is/indexen.jsp?id=summary) for assistance in the ascertainment of the Icelandic patients with lung cancer. The ICR study made use of genotyping data from the Wellcome Trust Case-Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. We acknowledge The Cancer Genome Atlas (TCGA) for their contribution of lung cancer genomic data to this study (TCGA Project Number 3230). We also acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. This study was supported by the NIH (U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996 and 5R01CA121197). The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362), National Cancer Research Network (NCRN), HEAL, Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. B.K. was the recipient of a Sir John Fisher Foundation PhD studentship. Work at ICR was also supported by NIH GM103534 and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed in Toronto was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The work performed at Heidelberg was supported by Deutsche Krebshilfe (70-2387 and 70-2919) and the German Federal Ministry of Education and Research (EPIC-Heidelberg). The work performed at IARC was supported by the Institut National du Cancer, France, the European Community (LSHG-CT-2005-512113), the Norwegian Cancer Association, the Functional Genomics Programme of Research Council of Norway, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the NIH (R01-CA111703 and UO1-CA63673), the Fred Hutchinson Cancer Research Center, the US NCI (R01 CA092039), an FP7 grant (REGPOT 245536), the Estonian Government (SF0180142s08), the EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure{\textquoteright}s Roadmap and the University of Tartu (SP1GVARENG) and an IARC Postdoctoral Fellowship (M.N.T.). Work at the NCI was supported by the Intramural Research Program of the NIH, the NCI, US Public Health Service contracts NCI (N01-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476 and NO1-CN-25404), the American Cancer Society, the NIH Genes, Environment and Health Initiative in part by HG-06-033-NCI-01 and RO1HL091172-01, genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446). Work was also supported by NIH grants (P50 CA70907, R01CA121197, RO1 CA127219, U19 CA148127 and RO1 CA55769) and a Cancer Prevention Research Institute of Texas grant (RP100443). Genotyping was provided by the Center for Inherited Disease Research (CIDR). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Icelandic study was supported in part by NIH DA17932.",

year = "2014",

doi = "10.1038/ng.3002",

language = "English",

volume = "46",

pages = "736--741",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "7",

}

Wang, Y, McKay, JD, Rafnar, T, Wang, Z, Timofeeva, MN, Broderick, P, Zong, X, Laplana, M, Wei, Y, Han, Y, Lloyd, A, Delahaye-Sourdeix, M, Chubb, D, Gaborieau, V, Wheeler, W, Chatterjee, N, Thorleifsson, G, Sulem, P, Liu, G, Kaaks, R, Henrion, M, Kinnersley, B, Vallée, M, Lecalvez-Kelm, F, Stevens, VL, Gapstur, SM, Chen, WV, Zaridze, D, Szeszenia-Dabrowska, N, Lissowska, J, Rudnai, P, Fabianova, E, Mates, D, Bencko, V, Foretova, L, Janout, V, Krokan, HE, Gabrielsen, ME, Skorpen, F, Vatten, L, Njølstad, I, Chen, C, Goodman, G, Benhamou, S, Vooder, T, Välk, K, Nelis, M, Metspalu, A, Lener, M, Lubiński, J, Johansson, M, Vineis, P, Agudo, A, Clavel-Chapelon, F, Bueno-De-Mesquita, HB, Trichopoulos, D, Khaw, KT, Johansson, M, Weiderpass, E, Tjønneland, A, Riboli, E, Lathrop, M, Scelo, G, Albanes, D, Caporaso, NE, Ye, Y, Gu, J, Wu, X, Spitz, MR, Dienemann, H, Rosenberger, A, Su, L, Matakidou, A, Eisen, T, Stefansson, K, Risch, A, Chanock, SJ, Christiani, DC, Hung, RJ, Brennan, P, Landi, MT, Houlston, RS & Amos, CI 2014, 'Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer', Nature Genetics, vol. 46, no. 7, pp. 736-741. https://doi.org/10.1038/ng.3002

TY - JOUR

T1 - Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

AU - Wang, Yufei

AU - McKay, James D.

AU - Rafnar, Thorunn

AU - Wang, Zhaoming

AU - Timofeeva, Maria N.

AU - Broderick, Peter

AU - Zong, Xuchen

AU - Laplana, Marina

AU - Wei, Yongyue

AU - Han, Younghun

AU - Lloyd, Amy

AU - Delahaye-Sourdeix, Manon

AU - Chubb, Daniel

AU - Gaborieau, Valerie

AU - Wheeler, William

AU - Chatterjee, Nilanjan

AU - Thorleifsson, Gudmar

AU - Sulem, Patrick

AU - Liu, Geoffrey

AU - Kaaks, Rudolf

AU - Henrion, Marc

AU - Kinnersley, Ben

AU - Vallée, Maxime

AU - Lecalvez-Kelm, Florence

AU - Stevens, Victoria L.

AU - Gapstur, Susan M.

AU - Chen, Wei V.

AU - Zaridze, David

AU - Szeszenia-Dabrowska, Neonilia

AU - Lissowska, Jolanta

AU - Rudnai, Peter

AU - Fabianova, Eleonora

AU - Mates, Dana

AU - Bencko, Vladimir

AU - Foretova, Lenka

AU - Janout, Vladimir

AU - Krokan, Hans E.

AU - Gabrielsen, Maiken Elvestad

AU - Skorpen, Frank

AU - Vatten, Lars

AU - Njølstad, Inger

AU - Chen, Chu

AU - Goodman, Gary

AU - Benhamou, Simone

AU - Vooder, Tonu

AU - Välk, Kristjan

AU - Nelis, Mari

AU - Metspalu, Andres

AU - Lener, Marcin

AU - Lubiński, Jan

AU - Johansson, Mattias

AU - Vineis, Paolo

AU - Agudo, Antonio

AU - Clavel-Chapelon, Francoise

AU - Bueno-De-Mesquita, H. Bas

AU - Trichopoulos, Dimitrios

AU - Khaw, Kay Tee

AU - Johansson, Mikael

AU - Weiderpass, Elisabete

AU - Tjønneland, Anne

AU - Riboli, Elio

AU - Lathrop, Mark

AU - Scelo, Ghislaine

AU - Albanes, Demetrius

AU - Caporaso, Neil E.

AU - Ye, Yuanqing

AU - Gu, Jian

AU - Wu, Xifeng

AU - Spitz, Margaret R.

AU - Dienemann, Hendrik

AU - Rosenberger, Albert

AU - Su, Li

AU - Matakidou, Athena

AU - Eisen, Timothy

AU - Stefansson, Kari

AU - Risch, Angela

AU - Chanock, Stephen J.

AU - Christiani, David C.

AU - Hung, Rayjean J.

AU - Brennan, Paul

AU - Landi, Maria Teresa

AU - Houlston, Richard S.

AU - Amos, Christopher I.

N1 - Funding Information: We thank all individuals who participated in this study. We are also grateful to the patients, clinicians and allied health care professions. We thank Z. Chen and K. Boyle for sample handling and data management of the Toronto study, and L. Admas and L.R. Zhang for field recruitment. We thank L. Su, Y. Zhao, G. Liu, J. Wain, R. Heist and K. Asomaning for providing computing support at MDACC. We thank G. Thomas and Synergy Lyon Cancer (Lyon France) for high performance computing support and J. Olivier and A. Chabrier for IARC’s PGM ion torrent sequencing optimization and TaqMan genotyping, respectively. We thank D. Goldgar for sharing information from The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) on sequence variation in BRCA2 from familial breast cancer analysis. We acknowledge the Icelandic Cancer Registry (http://www. krabbameinsskra.is/indexen.jsp?id=summary) for assistance in the ascertainment of the Icelandic patients with lung cancer. The ICR study made use of genotyping data from the Wellcome Trust Case-Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. We acknowledge The Cancer Genome Atlas (TCGA) for their contribution of lung cancer genomic data to this study (TCGA Project Number 3230). We also acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. This study was supported by the NIH (U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996 and 5R01CA121197). The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362), National Cancer Research Network (NCRN), HEAL, Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. B.K. was the recipient of a Sir John Fisher Foundation PhD studentship. Work at ICR was also supported by NIH GM103534 and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed in Toronto was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The work performed at Heidelberg was supported by Deutsche Krebshilfe (70-2387 and 70-2919) and the German Federal Ministry of Education and Research (EPIC-Heidelberg). The work performed at IARC was supported by the Institut National du Cancer, France, the European Community (LSHG-CT-2005-512113), the Norwegian Cancer Association, the Functional Genomics Programme of Research Council of Norway, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the NIH (R01-CA111703 and UO1-CA63673), the Fred Hutchinson Cancer Research Center, the US NCI (R01 CA092039), an FP7 grant (REGPOT 245536), the Estonian Government (SF0180142s08), the EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure’s Roadmap and the University of Tartu (SP1GVARENG) and an IARC Postdoctoral Fellowship (M.N.T.). Work at the NCI was supported by the Intramural Research Program of the NIH, the NCI, US Public Health Service contracts NCI (N01-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476 and NO1-CN-25404), the American Cancer Society, the NIH Genes, Environment and Health Initiative in part by HG-06-033-NCI-01 and RO1HL091172-01, genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446). Work was also supported by NIH grants (P50 CA70907, R01CA121197, RO1 CA127219, U19 CA148127 and RO1 CA55769) and a Cancer Prevention Research Institute of Texas grant (RP100443). Genotyping was provided by the Center for Inherited Disease Research (CIDR). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Icelandic study was supported in part by NIH DA17932.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84903585835&partnerID=8YFLogxK

U2 - 10.1038/ng.3002

DO - 10.1038/ng.3002

M3 - Article

C2 - 24880342

AN - SCOPUS:84903585835

SN - 1061-4036

VL - 46

SP - 736

EP - 741

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

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