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Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis

Authors :
Sri V V Deevi
Henric Olsson
Carolina Haefliger
Maria Karlsson
Richard J. Allen
Susan J. Monkley
Louise V. Wain
Toby M. Maher
Daniel Muthas
A. Mackay
Philip L. Molyneaux
Adam Platt
Abhishek Nag
Glenda Lassi
Quanli Wang
Maria G. Belvisi
Dimitrios Vitsios
Lynne Murray
Gisli Jenkins
Sebastian Wasilewski
Kristina Ibáñez
Slavé Petrovski
Johan Mattsson
Simon Young
Ryan S. Dhindsa
Eleanor M. Wigmore
Source :
Communications Biology, Vol 4, Iss 1, Pp 1-8 (2021), Communications Biology
Publication Year :
2021
Publisher :
Nature Research, 2021.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87, 95% confidence interval: 2.03–4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10−20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.<br />Ryan Dhindsa et al. conducted an exome-wide association study to identify a rare variant in SPDL1 as a risk factor for idiopathic pulmonary fibrosis (IPF). Their findings implicate mitotic checkpoint signalling as a new mechanism underlying IPF.

Details

Language :
English
Database :
OpenAIRE
Journal :
Communications Biology, Vol 4, Iss 1, Pp 1-8 (2021), Communications Biology
Accession number :
edsair.doi.dedup.....400e1ca896fef45197cb0cae551425f5