Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Xuemei Ji; Yohan Bossé; Maria Teresa Landi; Jiang Gui; Xiangjun Xiao; David Qian; Philippe Joubert; Maxime Lamontagne; Yafang Li; Ivan Gorlov; Mariella de Biasi; Younghun Han; Olga Gorlova; Rayjean J. Hung; Xifeng Wu; James McKay; Xuchen Zong; Robert Carreras-Torres; David C. Christiani; Neil Caporaso; Mattias Johansson; Geoffrey Liu; Stig E. Bojesen; Loic Le Marchand; Demetrios Albanes; Heike Bickeböller; Melinda C. Aldrich; William S. Bush; Adonina Tardon; Gad Rennert; Chu Chen; 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 A. Bertazzi; Angela C. Pesatori; Yuanqing Ye; Nancy Diao; Li Su; Ruyang Zhang; Yonathan Brhane; Natasha Leighl; Jakob S. Johansen; Anders Mellemgaard; Walid Saliba; Christopher Haiman; Lynne Wilkens; Ana Fernandez-Somoano; Guillermo Fernandez-Tardon; Erik H.F.M. van der Heijden; Jin Hee Kim; Juncheng Dai; Zhibin Hu; Michael P.A. Davies; Michael W. Marcus; Hans Brunnström; Jonas Manjer; Olle Melander; David C. Muller; Kim Overvad; Antonia Trichopoulou; Rosario Tumino; Jennifer Doherty; Gary E. Goodman; Angela Cox; Fiona Taylor; Penella Woll; Irene Brüske; Judith Manz; Thomas Muley; Angela Risch; Albert Rosenberger; Kjell Grankvist; Mikael Johansson; Frances Shepherd; Ming Sound Tsao; Susanne M. Arnold; Eric B. Haura; Ciprian Bolca; Ivana Holcatova; Vladimir Janout; Milica Kontic; Jolanta Lissowska; Anush Mukeria; Simona Ognjanovic; Tadeusz M. Orlowski; Ghislaine Scelo; Beata Swiatkowska; David Zaridze; Per Bakke; Vidar Skaug; Shanbeh Zienolddiny; Eric J. Duell; Lesley M. Butler; Woon Puay Koh; Yu Tang Gao; Richard Houlston; John McLaughlin; Victoria Stevens; David C. Nickle; Ma’en Obeidat; Wim Timens; Bin Zhu; Lei Song; María Soler Artigas; Martin D. Tobin; Louise V. Wain; Fangyi Gu; Jinyoung Byun; Ahsan Kamal; Dakai Zhu; Rachel F. Tyndale; Wei Qi Wei; Stephen Chanock; Paul Brennan; Christopher I. Amos

doi:10.1038/s41467-018-05074-y

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella de Biasi, Younghun Han, Olga Gorlova, Rayjean J. Hung, Xifeng Wu, James McKay, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil CaporasoMattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, 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 A. Bertazzi, Angela C. Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H.F.M. van der Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P.A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Jennifer Doherty, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Irene Brüske, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J. Duell, Lesley M. Butler, Woon Puay Koh, Yu Tang Gao, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, Bin Zhu, Lei Song, María Soler Artigas, Martin D. Tobin, Louise V. Wain, Fangyi Gu, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Rachel F. Tyndale, Wei Qi Wei, Stephen Chanock, Paul Brennan, Christopher I. Amos

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

Original language	English
Article number	3221
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05074-y
State	Published - Dec 1 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) for the research of lung cancer (grants P30CA023108, P20GM103534, and R01LM012012); Transdisciplinary Research in Cancer of the Lung (TRICL) (grant U19CA148127); UICC American Cancer Society Beginning Investigators Fellowship funded by the Union for International Cancer Control (UICC) (to X.J.). CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN.CARET study was supported by NIH awards UM1 CA167462, UO1-CA6367307, CA111703, and R01 CA151989. The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by NIH grants CA092824, CA090578, and CA074386. The Multiethnic Cohort Study was partially supported by NIH grants CA164973, CA033619, CA63464, and CA148127. The MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. R.T is supported by a Canada Research Chair in Pharmacoge-nomics, CIHR grant (FDN-154294), and CAMH. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study was supported by NIH R01 CA144034 and UM1 CA182876. The Singapore Chinese Health Study (SCHS) was supported by NIH R01 CA144034 and UM1 CA182876. The TLC study has been supported in part by the James & Esther King Biomedical Research Program (09KN-15), NIH grant P50 CA119997 and P30CA76292. The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH, K07CA172294 and U01HG004798. The Copenhagen General Population Study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study was supported by NIH grant P20RR018787. The MDACC study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568), Cancer Prevention & Research Institute of Texas (RP130502), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. It is also supported by NIH grant UL1TR000117 and P30 CA177558 using Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre, and Weston Park Hospital Cancer Charity. F.T. was supported by a clinical PhD fellowship funded by the Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre. The authors at Laval would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL dataset at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l’Institut universitaire de cardiologie et de pneu-mologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP-123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The research undertaken by M.T., L.W., and M.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313).

Publisher Copyright:
© 2018, The Author(s).

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Cite this

Ji, X., Bossé, Y., Landi, M. T., Gui, J., Xiao, X., Qian, D., Joubert, P., Lamontagne, M., Li, Y., Gorlov, I., de Biasi, M., Han, Y., Gorlova, O., Hung, R. J., Wu, X., McKay, J., Zong, X., Carreras-Torres, R., Christiani, D. C., ... Amos, C. I. (2018). Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nature Communications, 9(1), Article 3221. https://doi.org/10.1038/s41467-018-05074-y

@article{6b930b6a6534485dabdf1e8f368c0825,

title = "Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk",

abstract = "Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.",

author = "Xuemei Ji and Yohan Boss{\'e} and Landi, {Maria Teresa} and Jiang Gui and Xiangjun Xiao and David Qian and Philippe Joubert and Maxime Lamontagne and Yafang Li and Ivan Gorlov and {de Biasi}, Mariella and Younghun Han and Olga Gorlova and Hung, {Rayjean J.} and Xifeng Wu and James McKay and Xuchen Zong and Robert Carreras-Torres and Christiani, {David C.} and Neil Caporaso and Mattias Johansson and Geoffrey Liu and Bojesen, {Stig E.} and {Le Marchand}, Loic and Demetrios Albanes and Heike Bickeb{\"o}ller and Aldrich, {Melinda C.} and Bush, {William S.} and Adonina Tardon and Gad Rennert and Chu Chen and Teare, {M. Dawn} and Field, {John K.} and Kiemeney, {Lambertus A.} and Philip Lazarus and Aage Haugen and Stephen Lam and Schabath, {Matthew B.} and Andrew, {Angeline S.} and Hongbing Shen and Hong, {Yun Chul} and Yuan, {Jian Min} and Bertazzi, {Pier A.} and Pesatori, {Angela C.} and Yuanqing Ye and Nancy Diao and Li Su and Ruyang Zhang and Yonathan Brhane and Natasha Leighl and Johansen, {Jakob S.} and Anders Mellemgaard and Walid Saliba and Christopher Haiman and Lynne Wilkens and Ana Fernandez-Somoano and Guillermo Fernandez-Tardon and {van der Heijden}, {Erik H.F.M.} and Kim, {Jin Hee} and Juncheng Dai and Zhibin Hu and Davies, {Michael P.A.} and Marcus, {Michael W.} and Hans Brunnstr{\"o}m and Jonas Manjer and Olle Melander and Muller, {David C.} and Kim Overvad and Antonia Trichopoulou and Rosario Tumino and Jennifer Doherty and Goodman, {Gary E.} and Angela Cox and Fiona Taylor and Penella Woll and Irene Br{\"u}ske and Judith Manz and Thomas Muley and Angela Risch and Albert Rosenberger and Kjell Grankvist and Mikael Johansson and Frances Shepherd and Tsao, {Ming Sound} and Arnold, {Susanne M.} and Haura, {Eric B.} and Ciprian Bolca and Ivana Holcatova and Vladimir Janout and Milica Kontic and Jolanta Lissowska and Anush Mukeria and Simona Ognjanovic and Orlowski, {Tadeusz M.} and Ghislaine Scelo and Beata Swiatkowska and David Zaridze and Per Bakke and Vidar Skaug and Shanbeh Zienolddiny and Duell, {Eric J.} and Butler, {Lesley M.} and Koh, {Woon Puay} and Gao, {Yu Tang} and Richard Houlston and John McLaughlin and Victoria Stevens and Nickle, {David C.} and Ma{\textquoteright}en Obeidat and Wim Timens and Bin Zhu and Lei Song and Artigas, {Mar{\'i}a Soler} and Tobin, {Martin D.} and Wain, {Louise V.} and Fangyi Gu and Jinyoung Byun and Ahsan Kamal and Dakai Zhu and Tyndale, {Rachel F.} and Wei, {Wei Qi} and Stephen Chanock and Paul Brennan and Amos, {Christopher I.}",

note = "Funding Information: This work was supported by National Institutes of Health (NIH) for the research of lung cancer (grants P30CA023108, P20GM103534, and R01LM012012); Transdisciplinary Research in Cancer of the Lung (TRICL) (grant U19CA148127); UICC American Cancer Society Beginning Investigators Fellowship funded by the Union for International Cancer Control (UICC) (to X.J.). CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologia y Salud P{\'u}blica. CIBERESP, SPAIN.CARET study was supported by NIH awards UM1 CA167462, UO1-CA6367307, CA111703, and R01 CA151989. The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by NIH grants CA092824, CA090578, and CA074386. The Multiethnic Cohort Study was partially supported by NIH grants CA164973, CA033619, CA63464, and CA148127. The MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. R.T is supported by a Canada Research Chair in Pharmacoge-nomics, CIHR grant (FDN-154294), and CAMH. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study was supported by NIH R01 CA144034 and UM1 CA182876. The Singapore Chinese Health Study (SCHS) was supported by NIH R01 CA144034 and UM1 CA182876. The TLC study has been supported in part by the James & Esther King Biomedical Research Program (09KN-15), NIH grant P50 CA119997 and P30CA76292. The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center{\textquoteright}s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH, K07CA172294 and U01HG004798. The Copenhagen General Population Study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study was supported by NIH grant P20RR018787. The MDACC study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568), Cancer Prevention & Research Institute of Texas (RP130502), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. It is also supported by NIH grant UL1TR000117 and P30 CA177558 using Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre, and Weston Park Hospital Cancer Charity. F.T. was supported by a clinical PhD fellowship funded by the Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre. The authors at Laval would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL dataset at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l{\textquoteright}Institut universitaire de cardiologie et de pneu-mologie de Qu{\'e}bec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP-123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The research undertaken by M.T., L.W., and M.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-05074-y",

language = "English",

volume = "9",

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Ji, X, Bossé, Y, Landi, MT, Gui, J, Xiao, X, Qian, D, Joubert, P, Lamontagne, M, Li, Y, Gorlov, I, de Biasi, M, Han, Y, Gorlova, O, Hung, RJ, Wu, X, McKay, J, Zong, X, Carreras-Torres, R, Christiani, DC, Caporaso, N, Johansson, M, Liu, G, Bojesen, SE, Le Marchand, L, Albanes, D, Bickeböller, H, Aldrich, MC, Bush, WS, Tardon, A, Rennert, G, Chen, C, Teare, MD, Field, JK, Kiemeney, LA, Lazarus, P, Haugen, A, Lam, S, Schabath, MB, Andrew, AS, Shen, H, Hong, YC, Yuan, JM, Bertazzi, PA, Pesatori, AC, Ye, Y, Diao, N, Su, L, Zhang, R, Brhane, Y, Leighl, N, Johansen, JS, Mellemgaard, A, Saliba, W, Haiman, C, Wilkens, L, Fernandez-Somoano, A, Fernandez-Tardon, G, van der Heijden, EHFM, Kim, JH, Dai, J, Hu, Z, Davies, MPA, Marcus, MW, Brunnström, H, Manjer, J, Melander, O, Muller, DC, Overvad, K, Trichopoulou, A, Tumino, R, Doherty, J, Goodman, GE, Cox, A, Taylor, F, Woll, P, Brüske, I, Manz, J, Muley, T, Risch, A, Rosenberger, A, Grankvist, K, Johansson, M, Shepherd, F, Tsao, MS, Arnold, SM, Haura, EB, Bolca, C, Holcatova, I, Janout, V, Kontic, M, Lissowska, J, Mukeria, A, Ognjanovic, S, Orlowski, TM, Scelo, G, Swiatkowska, B, Zaridze, D, Bakke, P, Skaug, V, Zienolddiny, S, Duell, EJ, Butler, LM, Koh, WP, Gao, YT, Houlston, R, McLaughlin, J, Stevens, V, Nickle, DC, Obeidat, M, Timens, W, Zhu, B, Song, L, Artigas, MS, Tobin, MD, Wain, LV, Gu, F, Byun, J, Kamal, A, Zhu, D, Tyndale, RF, Wei, WQ, Chanock, S, Brennan, P & Amos, CI 2018, 'Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk', Nature Communications, vol. 9, no. 1, 3221. https://doi.org/10.1038/s41467-018-05074-y

TY - JOUR

T1 - Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

AU - Ji, Xuemei

AU - Bossé, Yohan

AU - Landi, Maria Teresa

AU - Gui, Jiang

AU - Xiao, Xiangjun

AU - Qian, David

AU - Joubert, Philippe

AU - Lamontagne, Maxime

AU - Li, Yafang

AU - Gorlov, Ivan

AU - de Biasi, Mariella

AU - Han, Younghun

AU - Gorlova, Olga

AU - Hung, Rayjean J.

AU - Wu, Xifeng

AU - McKay, James

AU - Zong, Xuchen

AU - Carreras-Torres, Robert

AU - Christiani, David C.

AU - Caporaso, Neil

AU - Johansson, Mattias

AU - Liu, Geoffrey

AU - Bojesen, Stig E.

AU - Le Marchand, Loic

AU - Albanes, Demetrios

AU - Bickeböller, Heike

AU - Aldrich, Melinda C.

AU - Bush, William S.

AU - Tardon, Adonina

AU - Rennert, Gad

AU - Chen, Chu

AU - Teare, M. Dawn

AU - Field, John K.

AU - Kiemeney, Lambertus A.

AU - Lazarus, Philip

AU - Haugen, Aage

AU - Lam, Stephen

AU - Schabath, Matthew B.

AU - Andrew, Angeline S.

AU - Shen, Hongbing

AU - Hong, Yun Chul

AU - Yuan, Jian Min

AU - Bertazzi, Pier A.

AU - Pesatori, Angela C.

AU - Ye, Yuanqing

AU - Diao, Nancy

AU - Su, Li

AU - Zhang, Ruyang

AU - Brhane, Yonathan

AU - Leighl, Natasha

AU - Johansen, Jakob S.

AU - Mellemgaard, Anders

AU - Saliba, Walid

AU - Haiman, Christopher

AU - Wilkens, Lynne

AU - Fernandez-Somoano, Ana

AU - Fernandez-Tardon, Guillermo

AU - van der Heijden, Erik H.F.M.

AU - Kim, Jin Hee

AU - Dai, Juncheng

AU - Hu, Zhibin

AU - Davies, Michael P.A.

AU - Marcus, Michael W.

AU - Brunnström, Hans

AU - Manjer, Jonas

AU - Melander, Olle

AU - Muller, David C.

AU - Overvad, Kim

AU - Trichopoulou, Antonia

AU - Tumino, Rosario

AU - Doherty, Jennifer

AU - Goodman, Gary E.

AU - Cox, Angela

AU - Taylor, Fiona

AU - Woll, Penella

AU - Brüske, Irene

AU - Manz, Judith

AU - Muley, Thomas

AU - Risch, Angela

AU - Rosenberger, Albert

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Shepherd, Frances

AU - Tsao, Ming Sound

AU - Arnold, Susanne M.

AU - Haura, Eric B.

AU - Bolca, Ciprian

AU - Holcatova, Ivana

AU - Janout, Vladimir

AU - Kontic, Milica

AU - Lissowska, Jolanta

AU - Mukeria, Anush

AU - Ognjanovic, Simona

AU - Orlowski, Tadeusz M.

AU - Scelo, Ghislaine

AU - Swiatkowska, Beata

AU - Zaridze, David

AU - Bakke, Per

AU - Skaug, Vidar

AU - Zienolddiny, Shanbeh

AU - Duell, Eric J.

AU - Butler, Lesley M.

AU - Koh, Woon Puay

AU - Gao, Yu Tang

AU - Houlston, Richard

AU - McLaughlin, John

AU - Stevens, Victoria

AU - Nickle, David C.

AU - Obeidat, Ma’en

AU - Timens, Wim

AU - Zhu, Bin

AU - Song, Lei

AU - Artigas, María Soler

AU - Tobin, Martin D.

AU - Wain, Louise V.

AU - Gu, Fangyi

AU - Byun, Jinyoung

AU - Kamal, Ahsan

AU - Zhu, Dakai

AU - Tyndale, Rachel F.

AU - Wei, Wei Qi

AU - Chanock, Stephen

AU - Brennan, Paul

AU - Amos, Christopher I.

N1 - Funding Information: This work was supported by National Institutes of Health (NIH) for the research of lung cancer (grants P30CA023108, P20GM103534, and R01LM012012); Transdisciplinary Research in Cancer of the Lung (TRICL) (grant U19CA148127); UICC American Cancer Society Beginning Investigators Fellowship funded by the Union for International Cancer Control (UICC) (to X.J.). CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN.CARET study was supported by NIH awards UM1 CA167462, UO1-CA6367307, CA111703, and R01 CA151989. The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by NIH grants CA092824, CA090578, and CA074386. The Multiethnic Cohort Study was partially supported by NIH grants CA164973, CA033619, CA63464, and CA148127. The MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. R.T is supported by a Canada Research Chair in Pharmacoge-nomics, CIHR grant (FDN-154294), and CAMH. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study was supported by NIH R01 CA144034 and UM1 CA182876. The Singapore Chinese Health Study (SCHS) was supported by NIH R01 CA144034 and UM1 CA182876. The TLC study has been supported in part by the James & Esther King Biomedical Research Program (09KN-15), NIH grant P50 CA119997 and P30CA76292. The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH, K07CA172294 and U01HG004798. The Copenhagen General Population Study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study was supported by NIH grant P20RR018787. The MDACC study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568), Cancer Prevention & Research Institute of Texas (RP130502), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. It is also supported by NIH grant UL1TR000117 and P30 CA177558 using Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre, and Weston Park Hospital Cancer Charity. F.T. was supported by a clinical PhD fellowship funded by the Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre. The authors at Laval would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL dataset at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l’Institut universitaire de cardiologie et de pneu-mologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP-123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The research undertaken by M.T., L.W., and M.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

AB - Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

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U2 - 10.1038/s41467-018-05074-y

DO - 10.1038/s41467-018-05074-y

M3 - Article

C2 - 30104567

AN - SCOPUS:85051632965

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3221

ER -

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

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