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

Lookup NU author(s): Professor Dawn Teare



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2019.

For re-use rights please refer to the publisher's terms and conditions.


© 2019 The Author(s). Published by Oxford University Press. All rights reserved. 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.

Publication metadata

Author(s): 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 J-M, Field JK, Manjer J, Grankvist K, Le Marchand L, Teare MD, Schabath MB, Aldrich MC, Tsao M-S, 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

Publication type: Article

Publication status: Published

Journal: Carcinogenesis

Year: 2019

Volume: 40

Issue: 3

Pages: 432-440

Print publication date: 01/03/2019

Online publication date: 09/01/2019

Acceptance date: 22/12/2018

Date deposited: 09/01/2020

ISSN (print): 0143-3334

ISSN (electronic): 1460-2180

Publisher: Oxford University Press


DOI: 10.1093/carcin/bgy187

PubMed id: 30590402


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