Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

Jinyoung Byun; Younghun Han; Yafang Li; Jun Xia; Erping Long; Jiyeon Choi; Xiangjun Xiao; Meng Zhu; Wen Zhou; Ryan Sun; Yohan Bossé; Zhuoyi Song; Ann Schwartz; Christine Lusk; Thorunn Rafnar; Kari Stefansson; Tongwu Zhang; Wei Zhao; Rowland W. Pettit; Yanhong Liu; Xihao Li; Hufeng Zhou; Kyle M. Walsh; Ivan Gorlov; Olga Gorlova; Dakai Zhu; Susan M. Rosenberg; Susan Pinney; Joan E. Bailey-Wilson; Diptasri Mandal; Mariza de Andrade; Colette Gaba; James C. Willey; Ming You; Marshall Anderson; John K. Wiencke; Demetrius Albanes; Stephan Lam; Adonina Tardon; Chu Chen; Gary Goodman; Stig Bojeson; Hermann Brenner; Maria Teresa Landi; Stephen J. Chanock; Mattias Johansson; Thomas Muley; Angela Risch; H. Erich Wichmann; Heike Bickeböller; David C. Christiani; Gad Rennert; Susanne Arnold; John K. Field; Sanjay Shete; Loic Le Marchand; Olle Melander; Hans Brunnstrom; Geoffrey Liu; Angeline S. Andrew; Lambertus A. Kiemeney; Hongbing Shen; Shanbeh Zienolddiny; Kjell Grankvist; Mikael Johansson; Neil Caporaso; Angela Cox; Yun Chul Hong; Jian Min Yuan; Philip Lazarus; Matthew B. Schabath; Melinda C. Aldrich; Alpa Patel; Qing Lan; Nathaniel Rothman; Fiona Taylor; Linda Kachuri; John S. Witte; Lori C. Sakoda; Margaret Spitz; Paul Brennan; Xihong Lin; James McKay; Rayjean J. Hung; Christopher I. Amos

doi:10.1038/s41588-022-01115-x

Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

Jinyoung Byun
, Younghun Han
, Yafang Li
, Jun Xia
, Erping Long
, Jiyeon Choi
, Xiangjun Xiao
, Meng Zhu
, Wen Zhou
, Ryan Sun
, Yohan Bossé
, Zhuoyi Song
, Ann Schwartz
, Christine Lusk
, Thorunn Rafnar
, Kari Stefansson
, Tongwu Zhang
, Wei Zhao
, Rowland W. Pettit
, Yanhong Liu

Xihao Li, Hufeng Zhou, Kyle M. Walsh, Ivan Gorlov, Olga Gorlova, Dakai Zhu, Susan M. Rosenberg, Susan Pinney, Joan E. Bailey-Wilson, Diptasri Mandal, Mariza de Andrade, Colette Gaba, James C. Willey, Ming You, Marshall Anderson, John K. Wiencke, Demetrius Albanes, Stephan Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig Bojeson, Hermann Brenner, Maria Teresa Landi, Stephen J. Chanock, Mattias Johansson, Thomas Muley, Angela Risch, H. Erich Wichmann, Heike Bickeböller, David C. Christiani, Gad Rennert, Susanne Arnold, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Hongbing Shen, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Angela Cox, Yun Chul Hong, Jian Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Alpa Patel, Qing Lan, Nathaniel Rothman, Fiona Taylor, Linda Kachuri, John S. Witte, Lori C. Sakoda, Margaret Spitz, Paul Brennan, Xihong Lin, James McKay, Rayjean J. Hung, Christopher I. Amos

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

82 Scopus citations

Abstract

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

Original language	English
Pages (from-to)	1167-1177
Number of pages	11
Journal	Nature Genetics
Volume	54
Issue number	8
DOIs	https://doi.org/10.1038/s41588-022-01115-x
State	Published - Aug 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

Our study was supported by the National Institutes of Health (NIH) for Integrative Analysis of Lung Cancer Etiology and Risk (U19CA203654) and Sequencing Familial Lung Cancer (R01CA243483). C.I.A. is a Research Scholar of the Cancer Prevention Research Interest of Texas (CPRIT) award (RR170048). Functional studies were partially supported by NIH grants (R01CA250905 (S.M.R), CPRIT RR170048 (C.I.A) and DP1-AG072751 (S.M.R.)). This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT RP180672) and the NIH (CA125123 and RR024574) as well as the assistance of J.M. Sederstrom. 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. D.M. was supported by Department of Health and Human Services contracts HHSN26820100007C, HHSN268201700012C and 75N92020C00001. J.E.B. was supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. R.W.P. was supported by NIH T32ES027801. J.X. was supported by the National Institute of Environmental Health Sciences of the NIH under Award Number K99ES033259. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. We acknowledge the participants and investigators of INTEGRAL-ILCCO Consortium, Genetic Epidemiology of Lung Cancer Consortium (GELCC), FinnGen study and Kaiser Permanente Research Bank (KPRB) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort study. Our study was supported by the National Institutes of Health (NIH) for Integrative Analysis of Lung Cancer Etiology and Risk (U19CA203654) and Sequencing Familial Lung Cancer (R01CA243483). C.I.A. is a Research Scholar of the Cancer Prevention Research Interest of Texas (CPRIT) award (RR170048). Functional studies were partially supported by NIH grants (R01CA250905 (S.M.R), CPRIT RR170048 (C.I.A) and DP1-AG072751 (S.M.R.)). This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT RP180672) and the NIH (CA125123 and RR024574) as well as the assistance of J.M. Sederstrom. 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. D.M. was supported by Department of Health and Human Services contracts HHSN26820100007C, HHSN268201700012C and 75N92020C00001. J.E.B. was supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. R.W.P. was supported by NIH T32ES027801. J.X. was supported by the National Institute of Environmental Health Sciences of the NIH under Award Number K99ES033259. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. We acknowledge the participants and investigators of INTEGRAL-ILCCO Consortium, Genetic Epidemiology of Lung Cancer Consortium (GELCC), FinnGen study and Kaiser Permanente Research Bank (KPRB) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort study.

Funders	Funder number
FinnGen study and Kaiser Permanente Research Bank
GELCC
KPRB
International Lung Cancer Consortium
Sheffield Experimental Cancer Medicine Centre
Study of Lung Cancer Epidemiology in North Trent
Weston Park Hospital Cancer Charity
Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre
National Institutes of Health (NIH)	RR024574, R01CA243483, CA125123, CPRIT RR170048, CPRIT RP180672, DP1-AG072751
National Institutes of Health (NIH)
U.S. Department of Health and Human Services	HHSN268201700012C, 75N92020C00001, HHSN26820100007C
U.S. Department of Health and Human Services
National Human Genome Research Institute	T32ES027801
National Human Genome Research Institute
National Childhood Cancer Registry – National Cancer Institute	R01CA250905, U19CA203654, ZIACP010201
National Childhood Cancer Registry – National Cancer Institute
National Institutes of Health/National Institute of Environmental Health Sciences	K99ES033259
National Institutes of Health/National Institute of Environmental Health Sciences
Cancer Prevention and Research Institute of Texas
National Cancer Institute Division of Cancer Epidemiology and Genetics
Sheffield Hospitals Charity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/s41588-022-01115-x

Cite this

Byun, J., Han, Y., Li, Y., Xia, J., Long, E., Choi, J., Xiao, X., Zhu, M., Zhou, W., Sun, R., Bossé, Y., Song, Z., Schwartz, A., Lusk, C., Rafnar, T., Stefansson, K., Zhang, T., Zhao, W., Pettit, R. W., ... Amos, C. I. (2022). Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer. Nature Genetics, 54(8), 1167-1177. https://doi.org/10.1038/s41588-022-01115-x

@article{548f95d8832c4859994401366e2d1740,

title = "Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer",

abstract = "To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.",

author = "Jinyoung Byun and Younghun Han and Yafang Li and Jun Xia and Erping Long and Jiyeon Choi and Xiangjun Xiao and Meng Zhu and Wen Zhou and Ryan Sun and Yohan Boss{\'e} and Zhuoyi Song and Ann Schwartz and Christine Lusk and Thorunn Rafnar and Kari Stefansson and Tongwu Zhang and Wei Zhao and Pettit, \{Rowland W.\} and Yanhong Liu and Xihao Li and Hufeng Zhou and Walsh, \{Kyle M.\} and Ivan Gorlov and Olga Gorlova and Dakai Zhu and Rosenberg, \{Susan M.\} and Susan Pinney and Bailey-Wilson, \{Joan E.\} and Diptasri Mandal and \{de Andrade\}, Mariza and Colette Gaba and Willey, \{James C.\} and Ming You and Marshall Anderson and Wiencke, \{John K.\} and Demetrius Albanes and Stephan Lam and Adonina Tardon and Chu Chen and Gary Goodman and Stig Bojeson and Hermann Brenner and Landi, \{Maria Teresa\} and Chanock, \{Stephen J.\} and Mattias Johansson and Thomas Muley and Angela Risch and Wichmann, \{H. Erich\} and Heike Bickeb{\"o}ller and Christiani, \{David C.\} and Gad Rennert and Susanne Arnold and Field, \{John K.\} and Sanjay Shete and \{Le Marchand\}, Loic and Olle Melander and Hans Brunnstrom and Geoffrey Liu and Andrew, \{Angeline S.\} and Kiemeney, \{Lambertus A.\} and Hongbing Shen and Shanbeh Zienolddiny and Kjell Grankvist and Mikael Johansson and Neil Caporaso and Angela Cox and Hong, \{Yun Chul\} and Yuan, \{Jian Min\} and Philip Lazarus and Schabath, \{Matthew B.\} and Aldrich, \{Melinda C.\} and Alpa Patel and Qing Lan and Nathaniel Rothman and Fiona Taylor and Linda Kachuri and Witte, \{John S.\} and Sakoda, \{Lori C.\} and Margaret Spitz and Paul Brennan and Xihong Lin and James McKay and Hung, \{Rayjean J.\} and Amos, \{Christopher I.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = aug,

doi = "10.1038/s41588-022-01115-x",

language = "English",

volume = "54",

pages = "1167--1177",

number = "8",

}

Byun, J, Han, Y, Li, Y, Xia, J, Long, E, Choi, J, Xiao, X, Zhu, M, Zhou, W, Sun, R, Bossé, Y, Song, Z, Schwartz, A, Lusk, C, Rafnar, T, Stefansson, K, Zhang, T, Zhao, W, Pettit, RW, Liu, Y, Li, X, Zhou, H, Walsh, KM, Gorlov, I, Gorlova, O, Zhu, D, Rosenberg, SM, Pinney, S, Bailey-Wilson, JE, Mandal, D, de Andrade, M, Gaba, C, Willey, JC, You, M, Anderson, M, Wiencke, JK, Albanes, D, Lam, S, Tardon, A, Chen, C, Goodman, G, Bojeson, S, Brenner, H, Landi, MT, Chanock, SJ, Johansson, M, Muley, T, Risch, A, Wichmann, HE, Bickeböller, H, Christiani, DC, Rennert, G, Arnold, S, Field, JK, Shete, S, Le Marchand, L, Melander, O, Brunnstrom, H, Liu, G, Andrew, AS, Kiemeney, LA, Shen, H, Zienolddiny, S, Grankvist, K, Johansson, M, Caporaso, N, Cox, A, Hong, YC, Yuan, JM, Lazarus, P, Schabath, MB, Aldrich, MC, Patel, A, Lan, Q, Rothman, N, Taylor, F, Kachuri, L, Witte, JS, Sakoda, LC, Spitz, M, Brennan, P, Lin, X, McKay, J, Hung, RJ & Amos, CI 2022, 'Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer', Nature Genetics, vol. 54, no. 8, pp. 1167-1177. https://doi.org/10.1038/s41588-022-01115-x

TY - JOUR

T1 - Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

AU - Byun, Jinyoung

AU - Han, Younghun

AU - Li, Yafang

AU - Xia, Jun

AU - Long, Erping

AU - Choi, Jiyeon

AU - Xiao, Xiangjun

AU - Zhu, Meng

AU - Zhou, Wen

AU - Sun, Ryan

AU - Bossé, Yohan

AU - Song, Zhuoyi

AU - Schwartz, Ann

AU - Lusk, Christine

AU - Rafnar, Thorunn

AU - Stefansson, Kari

AU - Zhang, Tongwu

AU - Zhao, Wei

AU - Pettit, Rowland W.

AU - Liu, Yanhong

AU - Li, Xihao

AU - Zhou, Hufeng

AU - Walsh, Kyle M.

AU - Gorlov, Ivan

AU - Gorlova, Olga

AU - Zhu, Dakai

AU - Rosenberg, Susan M.

AU - Pinney, Susan

AU - Bailey-Wilson, Joan E.

AU - Mandal, Diptasri

AU - de Andrade, Mariza

AU - Gaba, Colette

AU - Willey, James C.

AU - You, Ming

AU - Anderson, Marshall

AU - Wiencke, John K.

AU - Albanes, Demetrius

AU - Lam, Stephan

AU - Tardon, Adonina

AU - Chen, Chu

AU - Goodman, Gary

AU - Bojeson, Stig

AU - Brenner, Hermann

AU - Landi, Maria Teresa

AU - Chanock, Stephen J.

AU - Johansson, Mattias

AU - Muley, Thomas

AU - Risch, Angela

AU - Wichmann, H. Erich

AU - Bickeböller, Heike

AU - Christiani, David C.

AU - Rennert, Gad

AU - Arnold, Susanne

AU - Field, John K.

AU - Shete, Sanjay

AU - Le Marchand, Loic

AU - Melander, Olle

AU - Brunnstrom, Hans

AU - Liu, Geoffrey

AU - Andrew, Angeline S.

AU - Kiemeney, Lambertus A.

AU - Shen, Hongbing

AU - Zienolddiny, Shanbeh

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Caporaso, Neil

AU - Cox, Angela

AU - Hong, Yun Chul

AU - Yuan, Jian Min

AU - Lazarus, Philip

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Patel, Alpa

AU - Lan, Qing

AU - Rothman, Nathaniel

AU - Taylor, Fiona

AU - Kachuri, Linda

AU - Witte, John S.

AU - Sakoda, Lori C.

AU - Spitz, Margaret

AU - Brennan, Paul

AU - Lin, Xihong

AU - McKay, James

AU - Hung, Rayjean J.

AU - Amos, Christopher I.

PY - 2022/8

Y1 - 2022/8

N2 - To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

AB - To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

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DO - 10.1038/s41588-022-01115-x

M3 - Article

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AN - SCOPUS:85135272569

SN - 1061-4036

VL - 54

SP - 1167

EP - 1177

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

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