Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
Authors: Ji Xuemei , Bossé Yohan , Landi Maria Teresa , Gui Jiang , Xiao Xiangjun , Qian David , Joubert Philippe , Lamontagne Maxime , Li Yafang , Gorlov Ivan , de Biasi Mariella , Han Younghun , Gorlova Olga , Hung Rayjean J. , Wu Xifeng , McKay James , Zong Xuchen , Carreras-Torres Robert , Christiani David C. , Caporaso Neil , Johansson Mattias , Liu Geoffrey , Bojesen Stig E. , Le Marchand Loic , Albanes Demetrios , Bickeböller Heike , Aldrich Melinda C. , Bush William S. , Tardon Adonina , Rennert Gad , Chen Chu , Teare M. Dawn , Field John K. , Kiemeney Lambertus A. , Lazarus Philip , Haugen Aage , Lam Stephen , Schabath Matthew B. , Andrew Angeline S. , Shen Hongbing , Hong Yun-Chul , Yuan Jian-Min , Bertazzi Pier A. , Pesatori Angela C. , Ye Yuanqing , Diao Nancy , Su Li , Zhang Ruyang , Brhane Yonathan , Leighl Natasha , Johansen Jakob S. , Mellemgaard Anders , Saliba Walid , Haiman Christopher , Wilkens Lynne , Fernandez-Somoano Ana , Fernandez-Tardon Guillermo , van der Heijden Erik H. F. M. , Kim Jin Hee , Dai Juncheng , Hu Zhibin , Davies Michael P. A. , Marcus Michael W. , Brunnström Hans , Manjer Jonas , Melander Olle , Muller David C. , Overvad Kim , Trichopoulou Antonia , Tumino Rosario , Doherty Jennifer , Goodman Gary E. , Cox Angela , Taylor Fiona , Woll Penella , Brüske Irene , Manz Judith , Muley Thomas , Risch Angela , Rosenberger Albert , Grankvist Kjell , Johansson Mikael , Shepherd Frances , Tsao Ming-Sound , Arnold Susanne M. , Haura Eric B. , Bolca Ciprian , Holcatova Ivana , Janout Vladimir , Kontic Milica , Lissowska Jolanta , Mukeria Anush , Ognjanovic Simona , Orlowski Tadeusz M. , Scelo Ghislaine , Swiatkowska Beata , Zaridze David , Bakke Per , Skaug Vidar , Zienolddiny Shanbeh , Duell Eric J. , Butler Lesley M. , Koh Woon-Puay , Gao Yu-Tang , Houlston Richard , McLaughlin John , Stevens Victoria , Nickle David C. , Obeidat Ma’en , Timens Wim , Zhu Bin , Song Lei , Artigas María Soler , Tobin Martin D. , Wain Louise V. , Gu Fangyi , Byun Jinyoung , Kamal Ahsan , Zhu Dakai , Tyndale Rachel F. , Wei Wei-Qi , Chanock Stephen , Brennan Paul , Amos Christopher I. 
Published: August 2018

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.