Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis
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Published version
Author(s)
Type
Journal Article
Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised 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 defence, telomere maintenance, signalling and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements: We conducted genome-wide analyses across three independent studies and meta-analysed 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. Main results: We identified and replicated three new genome-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 signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
Date Issued
2020-03-01
Date Acceptance
2019-11-07
Citation
American Journal of Respiratory and Critical Care Medicine, 2020, 201 (5), pp.564-574
ISSN
1073-449X
Publisher
American Thoracic Society
Start Page
564
End Page
574
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
201
Issue
5
Copyright Statement
© 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/).
licenses/by/4.0/).
Sponsor
Action for Pulmonary Fibrosis
National Institute for Health Research
British Lung Foundation
Identifier
https://www.atsjournals.org/doi/10.1164/rccm.201905-1017OC
Grant Number
n/a
CS-2013-13-017
C17-3
Subjects
Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
genetics
epidemiology
KIF15
MAD1L1
DEPTOR
VARIANTS
RISK
RTEL1
MUTATIONS
TELOMERES
DIAGNOSIS
SURVIVAL
REGION
EVENT
GAIN
DEPTOR
KIF15
MAD1L1
epidemiology
genetics
11 Medical and Health Sciences
Respiratory System
Publication Status
Published online
Article Number
rccm.201905-1017OC
Date Publish Online
2020-03-01