Systematic analyses of regulatory variants in DNase i hypersensitive sites identified two novel lung cancer susceptibility loci

Juncheng Dai; Zhihua Li; Christopher I. Amos; Rayjean J. Hung; Adonina Tardon; Angeline S. Andrew; Chu Chen; David C. Christiani; Demetrios Albanes; Erik H.F.M. Van Der Heijden; Eric J. Duell; Gad Rennert; James D. McKay; Jian Min Yuan; John K. Field; Jonas Manjer; Kjell Grankvist; Loic Le Marchand; M. Dawn Teare; Matthew B. Schabath; Melinda C. Aldrich; Ming Sound Tsao; Philip Lazarus; Stephen Lam; Stig E. Bojesen; Susanne Arnold; Xifeng Wu; Aage Haugen; Vladimir Janout; Mikael Johansson; Yonathan Brhane; Ana Fernandez-Somoano; Lambertus A. Kiemeney; Michael P.A. Davies; Shanbeh Zienolddiny; Zhibin Hu; Hongbing Shen

doi:10.1093/carcin/bgy187

Systematic analyses of regulatory variants in DNase i hypersensitive sites identified two novel lung cancer susceptibility loci

Juncheng Dai
, Zhihua Li
, Christopher I. Amos
, Rayjean J. Hung
, Adonina Tardon
, Angeline S. Andrew
, Chu Chen
, David C. Christiani
, Demetrios Albanes
, Erik H.F.M. Van Der Heijden
, Eric J. Duell
, Gad Rennert
, James D. McKay
, Jian Min Yuan
, John K. Field
, Jonas Manjer
, Kjell Grankvist
, Loic Le Marchand
, M. Dawn Teare
, Matthew B. Schabath

Melinda C. Aldrich, Ming Sound Tsao, Philip Lazarus, Stephen Lam, Stig E. Bojesen, Susanne Arnold, Xifeng Wu, Aage Haugen, Vladimir Janout, Mikael Johansson, Yonathan Brhane, Ana Fernandez-Somoano, Lambertus A. Kiemeney, Michael P.A. Davies, Shanbeh Zienolddiny, Zhibin Hu, Hongbing Shen

Pharmaceutical Sciences

Nanjing Medical University
First Affiliated Hospital of Nanjing Medical University
Dartmouth College
University of Toronto
University of Oviedo
Fred Hutchinson Cancer Research Center
Harvard University
National Institutes of Health
Radboud University Nijmegen
Institute Catala Oncologia
Clalit Health Services
International Agency for Research on Cancer
University of Pittsburgh
University of Liverpool
Lund University
Umeå University
Connecticut Agricultural Experiment Station
University of Sheffield
Moffitt Cancer Center
Vanderbilt University
University Health Network
Provincial Health Services Authority
University of Copenhagen
University of Kentucky
University of Texas MD Anderson Cancer Center
National Institute of Occupational Health
Palacký University Olomouc

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

10 Scopus citations

Abstract

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10^-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10^-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10^-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

Original language	English
Article number	bgy187
Pages (from-to)	432-440
Number of pages	9
Journal	Carcinogenesis
Volume	40
Issue number	3
DOIs	https://doi.org/10.1093/carcin/bgy187
State	Published - May 14 2019

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10.1093/carcin/bgy187

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Dai, J., Li, Z., Amos, C. I., Hung, R. J., Tardon, A., Andrew, A. S., Chen, C., Christiani, D. C., Albanes, D., Van Der Heijden, E. H. F. M., Duell, E. J., Rennert, G., McKay, J. D., Yuan, J. M., Field, J. K., Manjer, J., Grankvist, K., Le Marchand, L., Teare, M. D., ... Shen, H. (2019). Systematic analyses of regulatory variants in DNase i hypersensitive sites identified two novel lung cancer susceptibility loci. Carcinogenesis, 40(3), 432-440. Article bgy187. https://doi.org/10.1093/carcin/bgy187

@article{6b3462c694a64708b0354af9537c5878,

title = "Systematic analyses of regulatory variants in DNase i hypersensitive sites identified two novel lung cancer susceptibility loci",

abstract = "DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95\% confidence interval [95\% CI]: 1.10-1.24, P = 8.45 {\texttimes} 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95\% CI: 0.89-0.95, P = 1.02 {\texttimes} 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 {\texttimes} 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.",

author = "Juncheng Dai and Zhihua Li and Amos, \{Christopher I.\} and Hung, \{Rayjean J.\} and Adonina Tardon and Andrew, \{Angeline S.\} and Chu Chen and Christiani, \{David C.\} and Demetrios Albanes and \{Van Der Heijden\}, \{Erik H.F.M.\} and Duell, \{Eric J.\} and Gad Rennert and McKay, \{James D.\} and Yuan, \{Jian Min\} and Field, \{John K.\} and Jonas Manjer and Kjell Grankvist and \{Le Marchand\}, Loic and Teare, \{M. Dawn\} and Schabath, \{Matthew B.\} and Aldrich, \{Melinda C.\} and Tsao, \{Ming Sound\} and Philip Lazarus and Stephen Lam and Bojesen, \{Stig E.\} and Susanne Arnold and Xifeng Wu and Aage Haugen and Vladimir Janout and Mikael Johansson and Yonathan Brhane and Ana Fernandez-Somoano and Kiemeney, \{Lambertus A.\} and Davies, \{Michael P.A.\} and Shanbeh Zienolddiny and Zhibin Hu and Hongbing Shen",

year = "2019",

month = may,

day = "14",

doi = "10.1093/carcin/bgy187",

language = "English",

volume = "40",

pages = "432--440",

journal = "Carcinogenesis",

issn = "0143-3334",

publisher = "Oxford University Press",

number = "3",

}

Dai, J, Li, Z, Amos, CI, Hung, RJ, Tardon, A, Andrew, AS, Chen, C, Christiani, DC, Albanes, D, Van Der Heijden, EHFM, Duell, EJ, Rennert, G, McKay, JD, Yuan, JM, Field, JK, Manjer, J, Grankvist, K, Le Marchand, L, Teare, MD, Schabath, MB, Aldrich, MC, Tsao, MS, Lazarus, P, Lam, S, Bojesen, SE, Arnold, S, Wu, X, Haugen, A, Janout, V, Johansson, M, Brhane, Y, Fernandez-Somoano, A, Kiemeney, LA, Davies, MPA, Zienolddiny, S, Hu, Z & Shen, H 2019, 'Systematic analyses of regulatory variants in DNase i hypersensitive sites identified two novel lung cancer susceptibility loci', Carcinogenesis, vol. 40, no. 3, bgy187, pp. 432-440. https://doi.org/10.1093/carcin/bgy187

TY - JOUR

T1 - Systematic analyses of regulatory variants in DNase i hypersensitive sites identified two novel lung cancer susceptibility loci

AU - Dai, Juncheng

AU - Li, Zhihua

AU - Amos, Christopher I.

AU - Hung, Rayjean J.

AU - Tardon, Adonina

AU - Andrew, Angeline S.

AU - Chen, Chu

AU - Christiani, David C.

AU - Albanes, Demetrios

AU - Van Der Heijden, Erik H.F.M.

AU - Duell, Eric J.

AU - Rennert, Gad

AU - McKay, James D.

AU - Yuan, Jian Min

AU - Field, John K.

AU - Manjer, Jonas

AU - Grankvist, Kjell

AU - Le Marchand, Loic

AU - Teare, M. Dawn

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Tsao, Ming Sound

AU - Lazarus, Philip

AU - Lam, Stephen

AU - Bojesen, Stig E.

AU - Arnold, Susanne

AU - Wu, Xifeng

AU - Haugen, Aage

AU - Janout, Vladimir

AU - Johansson, Mikael

AU - Brhane, Yonathan

AU - Fernandez-Somoano, Ana

AU - Kiemeney, Lambertus A.

AU - Davies, Michael P.A.

AU - Zienolddiny, Shanbeh

AU - Hu, Zhibin

AU - Shen, Hongbing

PY - 2019/5/14

Y1 - 2019/5/14

N2 - DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

AB - DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

UR - https://www.scopus.com/pages/publications/85066163672

U2 - 10.1093/carcin/bgy187

DO - 10.1093/carcin/bgy187

M3 - Article

C2 - 30590402

AN - SCOPUS:85066163672

SN - 0143-3334

VL - 40

SP - 432

EP - 440

JO - Carcinogenesis

JF - Carcinogenesis

IS - 3

M1 - bgy187

ER -

Systematic analyses of regulatory variants in DNase i hypersensitive sites identified two novel lung cancer susceptibility loci

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