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

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

Pubmed ID: 30104567 RIS Download

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: P50 CA119997
  • Agency: NCI NIH HHS, United States
    Id: P30 CA023108
  • Agency: NCI NIH HHS, United States
    Id: P30 CA076292
  • Agency: NCI NIH HHS, United States
    Id: U01 CA063464
  • Agency: NCI NIH HHS, United States
    Id: P50 CA070907
  • Agency: NCI NIH HHS, United States
    Id: R01 CA111703
  • Agency: NCI NIH HHS, United States
    Id: UM1 CA182876
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR000117
  • Agency: NCI NIH HHS, United States
    Id: P20 CA090578
  • Agency: NCI NIH HHS, United States
    Id: U19 CA148127
  • Agency: NIGMS NIH HHS, United States
    Id: P20 GM103534
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR000445
  • Agency: NLM NIH HHS, United States
    Id: R01 LM012012
  • Agency: NCI NIH HHS, United States
    Id: R01 CA092824
  • Agency: NCI NIH HHS, United States
    Id: R35 CA197449
  • Agency: NCI NIH HHS, United States
    Id: UM1 CA164973
  • Agency: NCI NIH HHS, United States
    Id: U01 CA167462
  • Agency: NCI NIH HHS, United States
    Id: U19 CA203654
  • Agency: NCI NIH HHS, United States
    Id: R01 CA144034
  • Agency: NCRR NIH HHS, United States
    Id: P20 RR018787
  • Agency: NCRR NIH HHS, United States
    Id: S10 RR025141
  • Agency: NCI NIH HHS, United States
    Id: R01 CA074386
  • Agency: NCI NIH HHS, United States
    Id: R01 CA176568
  • Agency: NCI NIH HHS, United States
    Id: K07 CA172294
  • Agency: NCI NIH HHS, United States
    Id: R01 CA063464
  • Agency: NCI NIH HHS, United States
    Id: P01 CA033619
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL133786
  • Agency: NCI NIH HHS, United States
    Id: P30 CA177558
  • Agency: NCI NIH HHS, United States
    Id: P50 CA090578
  • Agency: NHGRI NIH HHS, United States
    Id: U01 HG004798
  • Agency: NCI NIH HHS, United States
    Id: R01 CA151989
  • Agency: World Health Organization, International
    Id: 001
  • Agency: Wellcome Trust, United Kingdom
    Id: 202849/Z/16/Z
  • Agency: NCI NIH HHS, United States
    Id: UM1 CA167462
  • Agency: NCI NIH HHS, United States
    Id: U01 CA164973

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This is a list of tools and resources that we have found mentioned in this publication.


GeneCards (tool)

RRID:SCR_002773

Database of human genes that provides concise genomic, proteomic, transcriptomic, genetic and functional information on all known and predicted human genes. Information featured in GeneCards includes orthologies, disease relationships, mutations and SNPs, gene expression, gene function, pathways, protein-protein interactions, related drugs and compounds and direct links to cutting edge research reagents and tools such as antibodies, recombinant proteins, clones, expression assays and RNAi reagents.

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Cytoscape (tool)

RRID:SCR_003032

Software platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.

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Gene Set Enrichment Analysis (tool)

RRID:SCR_003199

Software package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.

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QuickGO (tool)

RRID:SCR_004608

A web-based browser for Gene Ontology terms and annotations, which is provided by the UniProtKB-GOA group at the EBI. It is able to offer a range of facilities including bulk downloads of GO annotation data which can be extensively filtered by a range of different parameters and GO slim set generation. The software for QuickGO is freely available under the Apache 2 license. QuickGO can supply GO term information and GO annotation data via REST web services.

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International Agency for Research on Cancer (tool)

RRID:SCR_005422

The International Agency for Research on Cancer (IARC) is part of the World Health Organization. IARC''s mission is to coordinate and conduct research on the causes of human cancer, the mechanisms of carcinogenesis, and to develop scientific strategies for cancer prevention and control. The Agency is involved in both epidemiological and laboratory research and disseminates scientific information through publications, meetings, courses, and fellowships.

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BioCarta Pathways (tool)

RRID:SCR_006917

BioCarta Pathways allows users to observe how genes interact in dynamic graphical models. Online maps available within this resource depict molecular relationships from areas of active research. In an open source approach, this community-fed forum constantly integrates emerging proteomic information from the scientific community. It also catalogs and summarizes important resources providing information for over 120,000 genes from multiple species. Find both classical pathways as well as current suggestions for new pathways.

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Statistical Analysis System (tool)

RRID:SCR_008567

Software platform to explore, analyze and visualize data. SAS 9.4 is part of SAS Platform. Standardized data governance and management from statistical software company SAS.

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1000 Genomes Project and AWS (tool)

RRID:SCR_008801

A dataset containing the full genomic sequence of 1,700 individuals, freely available for research use. The 1000 Genomes Project is an international research effort coordinated by a consortium of 75 companies and organizations to establish the most detailed catalogue of human genetic variation. The project has grown to 200 terabytes of genomic data including DNA sequenced from more than 1,700 individuals that researchers can now access on AWS for use in disease research free of charge. The dataset containing the full genomic sequence of 1,700 individuals is now available to all via Amazon S3. The data can be found at: http://s3.amazonaws.com/1000genomes The 1000 Genomes Project aims to include the genomes of more than 2,662 individuals from 26 populations around the world, and the NIH will continue to add the remaining genome samples to the data collection this year. Public Data Sets on AWS provide a centralized repository of public data hosted on Amazon Simple Storage Service (Amazon S3). The data can be seamlessly accessed from AWS services such Amazon Elastic Compute Cloud (Amazon EC2) and Amazon Elastic MapReduce (Amazon EMR), which provide organizations with the highly scalable compute resources needed to take advantage of these large data collections. AWS is storing the public data sets at no charge to the community. Researchers pay only for the additional AWS resources they need for further processing or analysis of the data. All 200 TB of the latest 1000 Genomes Project data is available in a publicly available Amazon S3 bucket. You can access the data via simple HTTP requests, or take advantage of the AWS SDKs in languages such as Ruby, Java, Python, .NET and PHP. Researchers can use the Amazon EC2 utility computing service to dive into this data without the usual capital investment required to work with data at this scale. AWS also provides a number of orchestration and automation services to help teams make their research available to others to remix and reuse. Making the data available via a bucket in Amazon S3 also means that customers can crunch the information using Hadoop via Amazon Elastic MapReduce, and take advantage of the growing collection of tools for running bioinformatics job flows, such as CloudBurst and Crossbow.

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EnrichmentMap (tool)

RRID:SCR_016052

Source code of a Cytoscape plugin for functional enrichment visualization. It organizes gene-sets, such as pathways and Gene Ontology terms, into a network to reveal which mutually overlapping gene-sets cluster together.

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PLINK (tool)

RRID:SCR_001757

Open source whole genome association analysis toolset, designed to perform range of basic, large scale analyses in computationally efficient manner. Used for analysis of genotype/phenotype data. Through integration with gPLINK and Haploview, there is some support for subsequent visualization, annotation and storage of results. PLINK 1.9 is improved and second generation of the software.

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DAVID (tool)

RRID:SCR_001881

Bioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.

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Promega (tool)

RRID:SCR_006724

An Antibody supplier

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IMPUTE (tool)

RRID:SCR_009245

Software application for estimating (imputing) unobserved genotypes in SNP association studies. The program is designed to work seamlessly with the output of the genotype calling program CHIAMO and the population genetic simulator HAPGEN, and it produces output that can be analyzed using the program SNPTEST. (entry from Genetic Analysis Software)

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SNPTEST (tool)

RRID:SCR_009406

Software program for the analysis of single SNP association in genome-wide studies. The tests implemented can cater for binary (case-control) and quantitative phenotypes, can condition upon an arbitrary set of covariates and properly account for the uncertainty in genotypes. The program is designed to work seamlessly with the output of both the genotype calling program CHIAMO, the genotype imputation program IMPUTE and the program GTOOL. This program was used in the analysis of the 7 genome-wide association studies carried out by the Wellcome Trust Case-Control Consortium (WTCCC). (entry from Genetic Analysis Software)

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KEGG (tool)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

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