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Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Sin, Don D; O'Connor, George T; Newell Jr., John D; Allen, Richard J; Guillen-Guio, Beatriz; Oldham, Justin M; Ma, Shwu Fan; Dressen, Amy; Paynton, Megan L; Kraven, Luke M; Obeidat, Ma'en; Li, Xuan; Ng, Michael; Braybrooke, Rebecca; Molina-Molina, Maria; Hobbs, Brian D; Putman, Rachel K; Sakornsakolpat, Phuwanat; Booth, Helen L.; Fahy, William A; Hart, Simon P; Hill, Mike R; Hirani, Nik; Hubbard, Richard B.; McAnulty, Robin J; Millar, Ann B; Navaratnam, Vidyia; Oballa, Eunice; Parfrey, Helen; Saini, Gauri; Whyte, Moira K. B.; Zhang, Yingze; Kaminski, Naftali; Adegunsoye, Ayodeji; Strek, Mary E.; Neighbors, Margaret; Sheng, Xuting R.; Gudmundsson, Gunnar; Gudnason, Vilmundur; Hatabu, Hiroto; Lederer, David J; Manichaikul, Ani; Newell, Jr., John D.; O'Connor, George T.; Ortega, Victor E; Xu, Hanfei; Fingerlin, Tasha E; Bossé, Yohan; Hao, Ke; Joubert, Philippe; Nickle, David C; Sin, Don D.; Timens, Wim; Furniss, Dominic; Morris, Andrew P; Zondervan, Krina; Hall, Ian P.; Sayers, Ian; Tobin...

Authors

Don D Sin

George T O'Connor

John D Newell Jr.

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

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, Jr.

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 Zondervan

Ian P. Hall

Ian Sayers

Martin D Tobin

Toby M. Maher

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



Abstract

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

Citation

Sin, D. D., O'Connor, G. T., Newell Jr., J. D., Allen, R. J., Guillen-Guio, B., Oldham, J. M., …Wain, L. V. (2020). Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 201(5), 564-574. https://doi.org/10.1164/rccm.201905-1017OC

Journal Article Type Article
Acceptance Date Nov 7, 2019
Online Publication Date Nov 11, 2019
Publication Date Mar 1, 2020
Deposit Date Nov 13, 2019
Publicly Available Date Mar 28, 2024
Journal American Journal of Respiratory and Critical Care Medicine
Print ISSN 1073-449X
Electronic ISSN 1535-4970
Publisher American Thoracic Society
Peer Reviewed Peer Reviewed
Volume 201
Issue 5
Pages 564-574
DOI https://doi.org/10.1164/rccm.201905-1017OC
Keywords Genetics; Epidemiology; KIF15; MAD1L1; DEPTOR
Public URL https://hull-repository.worktribe.com/output/3156921
Publisher URL https://www.atsjournals.org/doi/abs/10.1164/rccm.201905-1017OC

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Copyright Statement
Copyright © 2020 by the American Thoracic Society. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/
licenses/by/4.0/).





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