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

Ryan S Dhindsa,Alex Mackay,Simon Young,Abhishek Nag,P.l Molyneaux ,Richard J Allen ,Lynne A Murray ,Sebastian Wasilewski,Maria G Belvisi,Glenda Lassi,Kristina Ibáñez ,Susan J Monkley ,Maria Karlsson,Daniel Muthas,Henric Olsson,Eleanor M Wigmore,Gisli Jenkins,Toby M Maher,Dimitrios Vitsios,Sri V V Deevi ,Louise V Wain,Quanli Wang,Carolina Haefliger,Adam Platt,Johan Mattsson,Slavé Petrovski

doi:10.1038/s42003-021-01910-y

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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring
There might be some individuals among the controls that will eventually develop IPF, we expect this error rate to be at most 0.02% given the incidence of IPF in the general European population[9]
Our exome-wide association study unveiled a missense variant in SPDL1 as a novel genetic risk factor for IPF. This variant, which is rare among non-Finnish European controls, confers a larger effect size than more common IPF risk alleles, with the exception of the MUC5B allele

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Genome-wide association studies (GWAS) of individuals with sporadic IPF have implicated common variants at several loci containing genes related to lung defence, telomere maintenance, cell-cell adhesion, mTOR signalling, and mitotic spindle assembly[4]. Despite the remarkable progress in identifying both rare and common variant signals, the underlying genetic predisposition remains unknown for the majority of IPF patients. We conducted the largest exome-based case-control analysis to date by using generation sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls screened for nonrespiratory disease. This large sample size allowed us to test for both variant- and gene-level associations across the allele frequency spectrum. Some of the results of these studies have been previously reported in the form of an abstract[8]

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