Publication:
Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Issued Date

2020-03-01

Resource Type

Article

ISSN

15354970
1073449X

DOI

10.1164/rccm.201905-1017OC

Other identifier(s)

2-s2.0-85080088253

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

American Journal of Respiratory and Critical Care Medicine. Vol.201, No.5 (2020), 564-574

Suggested Citation

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 Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine. Vol.201, No.5 (2020), 564-574. doi:10.1164/rccm.201905-1017OC Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/53750

Research Projects

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Thesis

Title

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Author(s)

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

Other Contributor(s)

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
 UCL
 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

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.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/53750

Collections

Scopus 2020