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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.

SUBMITTER: Ji X

PROVIDER: S-EPMC6089967 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Ji Xuemei X Bossé Yohan Y Landi Maria Teresa MT Gui Jiang J Xiao Xiangjun X Qian David D Joubert Philippe P Lamontagne Maxime M Li Yafang Y Gorlov Ivan I de Biasi Mariella M Han Younghun Y Gorlova Olga O Hung Rayjean J RJ Wu Xifeng X McKay James J Zong Xuchen X Carreras-Torres Robert R Christiani David C DC Caporaso Neil N Johansson Mattias M Liu Geoffrey G Bojesen Stig E SE Le Marchand Loic L Albanes Demetrios D Bickeböller Heike H Aldrich Melinda C MC Bush William S WS Tardon Adonina A Rennert Gad G Chen Chu C Teare M Dawn MD Field John K JK Kiemeney Lambertus A LA Lazarus Philip P Haugen Aage A Lam Stephen S Schabath Matthew B MB Andrew Angeline S AS Shen Hongbing H Hong Yun-Chul YC Yuan Jian-Min JM Bertazzi Pier A PA Pesatori Angela C AC Ye Yuanqing Y Diao Nancy N Su Li L Zhang Ruyang R Brhane Yonathan Y Leighl Natasha N Johansen Jakob S JS Mellemgaard Anders A Saliba Walid W Haiman Christopher C Wilkens Lynne L Fernandez-Somoano Ana A Fernandez-Tardon Guillermo G van der Heijden Erik H F M EHFM Kim Jin Hee JH Dai Juncheng J Hu Zhibin Z Davies Michael P A MPA Marcus Michael W MW Brunnström Hans H Manjer Jonas J Melander Olle O Muller David C DC Overvad Kim K Trichopoulou Antonia A Tumino Rosario R Doherty Jennifer J Goodman Gary E GE Cox Angela A Taylor Fiona F Woll Penella P Brüske Irene I Manz Judith J Muley Thomas T Risch Angela A Rosenberger Albert A Grankvist Kjell K Johansson Mikael M Shepherd Frances F Tsao Ming-Sound MS Arnold Susanne M SM Haura Eric B EB Bolca Ciprian C Holcatova Ivana I Janout Vladimir V Kontic Milica M Lissowska Jolanta J Mukeria Anush A Ognjanovic Simona S Orlowski Tadeusz M TM Scelo Ghislaine G Swiatkowska Beata B Zaridze David D Bakke Per P Skaug Vidar V Zienolddiny Shanbeh S Duell Eric J EJ Butler Lesley M LM Koh Woon-Puay WP Gao Yu-Tang YT Houlston Richard R McLaughlin John J Stevens Victoria V Nickle David C DC Obeidat Ma'en M Timens Wim W Zhu Bin B Song Lei L Artigas María Soler MS Tobin Martin D MD Wain Louise V LV Gu Fangyi F Byun Jinyoung J Kamal Ahsan A Zhu Dakai D Tyndale Rachel F RF Wei Wei-Qi WQ Chanock Stephen S Brennan Paul P Amos Christopher I CI

Nature communications 20180813 1

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 combine ...[more]

PMID: 30104567

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Project description:BackgroundThe association between polymorphisms on 15q25.1 and lung cancer has been widely evaluated; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two polymorphisms (CHRNA3 gene: rs1051730 and AGPHD1 gene: rs8034191) on 15q25.1.MethodsData were extracted from 15 and 14 studies on polymorphisms rs1051730 and rs8034191 involving 12301/14000 and 14075/12873 lung cancer cases/controls, respectively. The random-effects model was applied, addressing heterogeneity and publication bias.ResultsThe two polymorphisms followed Hardy-Weinberg equilibrium for all studies (P>0.05). For rs1051730-G/A, carriers of A allele had a 36% increased risk for lung cancer (95% confidence interval [CI]: 1.27-1.46; P<0.0005), without heterogeneity (P = 0.258) or publication bias (P(Egger) = 0.462). For rs8034191-T/C, the allelic contrast indicated that C allele conferred a 23% increased risk for lung cancer (95% CI: 1.08-1.4; P = 0.002), with significant heterogeneity (P<0.0005), without publication bias (P(Egger) = 0.682). Subgroup analyses suggested that the between-study heterogeneity was derived from ethnicity, study design, matched information, and lung cancer subtypes. For example, the association of polymorphisms rs1051730 and rs8034191 with lung cancer was heterogeneous between Caucasians (OR = 1.32 and 1.22; 95% CI: 1.25-1.44 and 1.05-1.42; P<0.0005 and 0.008, respectively) and East Asians (OR = 1.51 and 1.03; 95% CI: 0.76-3 and 0.47-2.27; P = 0.237 and 0.934, respectively) under the allelic model, and this association was relatively strengthened under the dominant model. There was no observable publication bias for both polymorphisms.ConclusionsOur findings demonstrated that CHRNA3 gene rs1051730-A allele and AGPHD1 gene rs8034191-T allele might be risk-conferring factors for the development of lung cancer in Caucasians, but not in East-Asians.

Project description:Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

Dataset Information

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

Publications

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

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