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Title: Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis
Authors: Richard J. Allen
Beatriz Guillen-Guio
Justin M. Oldham
Shwu Fan Ma
Amy Dressen
Megan L. Paynton
Luke M. Kraven
Ma'en Obeidat
Xuan Li
Michael Ng
Rebecca Braybrooke
Maria Molina-Molina
Brian D. Hobbs
Rachel K. Putman
Phuwanat Sakornsakolpat
Helen L. Booth
William A. Fahy
Simon P. Hart
Mike R. Hill
Nik Hirani
Richard B. Hubbard
Robin J. McAnulty
Ann B. Millar
Vidyia Navaratnam
Eunice Oballa
Helen Parfrey
Gauri Saini
Moira K.B. Whyte
Yingze Zhang
Naftali Kaminski
Ayodeji Adegunsoye
Mary E. Strek
Margaret Neighbors
Xuting R. Sheng
Gunnar Gudmundsson
Vilmundur Gudnason
Hiroto Hatabu
David J. Lederer
Ani Manichaikul
John D. Newell
George T. O'Connor
Victor E. Ortega
Hanfei Xu
Tasha E. Fingerlin
Yohan Bossé
Ke Hao
Philippe Joubert
David C. Nickle
Don D. Sin
Wim Timens
Dominic Furniss
Andrew P. Morris
Krina T. Zondervan
Ian P. Hall
Ian Sayers
Martin D. Tobin
M. Toby
Michael H. Cho
Gary M. Hunninghake
David A. Schwartz
Brian L. Yaspan
Philip L. Molyneaux
Carlos Flores
Imre Noth
R. Gisli Jenkins
Louise V. Wain
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias
National Jewish Health
Wellcome Trust Centre for Human Genetics
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval
Instituto Tecnológico y de Energías Renovables, S.A.
Landspitali University Hospital
Icelandic Heart Association
Haskoli Islands
Papworth Hospital, NHS Foundation Trust
University of Leicester
Wake Forest School of Medicine
The University of Chicago
Columbia University Irving Medical Center
University of Edinburgh
University of Oxford
Genentech Incorporated
Institut d'Investigació Biomedica de Bellvitge
Castle Hill Hospital
Nottingham University Hospitals NHS Trust
Framingham Heart Study
University of Virginia
University of Liverpool
University of Bristol
GlaxoSmithKline plc.
Boston University
Yale School of Medicine
Brigham and Women's Hospital
University of Pittsburgh
University of Washington, Seattle
University of Nottingham
University of California, Davis
Icahn School of Medicine at Mount Sinai
Vagelos College of Physicians and Surgeons
Faculty of Medicine, Siriraj Hospital, Mahidol University
National Heart and Lung Institute
The University of British Columbia
University of Colorado at Denver
University of Iowa Carver College of Medicine
Glenfield Hospital
Royal Brompton Hospital
Merck & Co., Inc.
University of Groningen, University Medical Center Groningen
University of Manchester
Universidad de la Laguna
Universitat de Barcelona
Groningen Research Institute for Asthma and COPD
Hospital Ntra
Keywords: Medicine
Issue Date: 1-Mar-2020
Citation: American Journal of Respiratory and Critical Care Medicine. Vol.201, No.5 (2020), 564-574
Abstract: © 2020 by the American Thoracic Society. Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated threenewgenome-wide significant (P<5×10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
ISSN: 15354970
Appears in Collections:Scopus 2020

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