Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer
Year: 2018
Type: article
Abstract: BACKGROUND: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
DOI: 10.1093/jnci/djy155
Authors: Naomi Walsh, Han Zhang, Paula L Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J Childs, Irene Collins, Zhaoming Wang, Alan A Arslan, Laura Beane-Freeman, Paige M Bracci, Paul Brennan, Federico Canzian, Eric J Duell, Steven Gallinger, Graham G Giles, Michael Goggins, Gary E Goodman, Phyllis J Goodman, Rayjean J Hung, Charles Kooperberg, Robert C Kurtz, Núria Malats, Loic LeMarchand, Rachel E Neale, Sara H Olson, Ghislaine Scelo, Xiao O Shu, Stephen K Van Den Eeden, Kala Visvanathan, Emily White, Wei Zheng, PanScan and PanC4 consortia, Demetrius Albanes, Gabriella Andreotti, Ana Babic, William R Bamlet, Sonja I Berndt, Ayelet Borgida, Marie-Christine Boutron-Ruault, Lauren Brais, Paul Brennan, Bas Bueno-de-Mesquita, Julie Buring, Kari G Chaffee, Stephen Chanock, Sean Cleary, Michelle Cotterchio, Lenka Foretova, Charles Fuchs, J Michael M Gaziano, Edward Giovannucci, Michael Goggins, Thilo Hackert, Christopher Haiman, Patricia Hartge, Manal Hasan, Kathy J Helzlsouer, Joseph Herman, Ivana Holcatova, Elizabeth A Holly, Robert Hoover, Rayjean J Hung, Vladimir Janout, Eric A Klein, Robert C Kurtz, Daniel Laheru, I-Min Lee, Lingeng Lu, Núria Malats, Satu Mannisto, Roger L Milne, Ann L Oberg, Irene Orlow, Alpa V Patel, Ulrike Peters, Miquel Porta, Francisco X Real, Nathaniel Rothman, Howard D Sesso, Gianluca Severi, Debra Silverman, Oliver Strobel, Malin Sund, Mark D Thornquist, Geoffrey S Tobias, Jean Wactawski-Wende, Nick Wareham, Elisabete Weiderpass, Nicolas Wentzensen, William Wheeler, Herbert Yu, Anne Zeleniuch-Jacquotte, Peter Kraft, Donghui Li, Eric J Jacobs, Gloria M Petersen, Brian M Wolpin, Harvey A Risch, Laufey T Amundadottir, Kai Yu, Alison P Klein, Rachael Z Stolzenberg-Solomon
Institutions: Dublin City University, National Institutes of Health, Division of Cancer Epidemiology and Genetics, United States Food and Drug Administration, Center for Drug Evaluation and Research, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, National Cancer Institute, St. Jude Children's Research Hospital, New York University, University of California, San Francisco, Centre international de recherche sur le cancer, German Cancer Research Center, Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, The University of Melbourne, Cancer Council Victoria, Monash University, Johns Hopkins Medicine, Fred Hutch Cancer Center, Memorial Sloan Kettering Cancer Center, Spanish National Cancer Research Centre, Centro de Investigación Biomédica en Red de Cáncer, University of Hawaii Cancer Center, QIMR Berghofer Medical Research Institute, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Kaiser Permanente, Kaiser Permanente Northern California, University of Washington, Dana-Farber Cancer Institute, Mayo Clinic, Inserm, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations, University of Malaya, National Institute for Public Health and the Environment, Imperial College London, Brigham and Women's Hospital, Harvard University, University of Toronto, Cancer Care Ontario, Masaryk Memorial Cancer Institute, Yale Cancer Center, VA Boston Healthcare System, University Hospital Heidelberg, University of Southern California, The University of Texas MD Anderson Cancer Center, Johns Hopkins Hospital, Charles University, University of Ostrava, Cleveland Clinic, Yale University, Finnish Institute for Health and Welfare, American Cancer Society, Universitat Autònoma de Barcelona, Hospital Del Mar, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Hospital del Mar Research Institute, Universitat Pompeu Fabra, Umeå University, University at Buffalo, State University of New York, University of Cambridge, MRC Epidemiology Unit, University of Helsinki, Karolinska Institutet, Cancer Registry of Norway, UiT The Arctic University of Norway, NYU Langone’s Laura and Isaac Perlmutter Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: World Health Organization, Health Research Board, National Institute for Health and Care Research, Irish Cancer Society, Science Foundation Ireland, National Institutes of Health, Medical Research Council, National Cancer Institute, National Center for Advancing Translational Sciences, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Intramural Research Program
Awards: G1044130170, G1324540468, G1680418936, G2309446911, Functional application of genomic variants to deliver personalized strategies for pancreatic cancer patients, PCPT and SELECT cohorts: Core Infrastructure Support for Cancer Research, G3503792436, G3734181317, G385201875, G386607036, The NYU Women's Health Study, Ontario Registry for Studies of Familial Colon Cancer, G4354666792, G4450071017, G4881700932, G557084418, G5788305929, G5888954722, G601631622, INFRASRUCTURE SUPPORT AND DATA ENHANCEMENTS FOR THE CARET BIOREPOSITORY, G675132270, G6777873208, G6957823285, THE CAROTENE AND RETINOL EFFICACY TRIAL (CARET), G7582124007, NIHR Senior Investigator Award, NIHR Senior Investigator Award, Cancer Center Support Grant
OpenAlex ID: W2905221341