Identification of a novel missense variant in SPDL1 associated with idiopathic pulmonary fibrosis
Ryan S Dhindsa,
Louise V Wain,
Eleanor M Wigmore,
Sri VV Deevi,
Toby M Maher,
Maria G. Belvisi,
R Gisli Jenkins,
Phil Michael Molyneaux,
Posted 29 Jun 2020
bioRxiv DOI: 10.1101/2020.06.29.178079
Posted 29 Jun 2020
Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite significant progress, the genetic determinants of this disease remain incompletely defined. Using next generation sequencing data from 752 individuals with sporadic IPF and 119,055 controls, we performed both variant- and gene-level analyses to identify novel IPF genetic risk factors. Our variant-level analysis revealed a novel rare missense variant in SPDL1 (NM_017785.5 p.Arg20Gln; p = 2.4 x 10-7, odds ratio = 2.87). This signal was independently replicated in the FinnGen cohort (combined p = 2.2 x 10-20), firmly associating this variant as a novel IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. Our results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need. ### Competing Interest Statement L.W. holds a GSK/British Lung Foundation Chair in Respiratory Research. The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. P.L.M. is supported by an Action for Pulmonary Fibrosis Mike Bray fellowship. T.M.M. is supported by a National Institute for Health Research Clinician Scientist Fellowship (NIHR ref: CS-2013-13-017) and is a British Lung Foundation Chair in Respiratory Research (C17-3). The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and eleven industry partners (AbbVie Inc, AstraZeneca UK Ltd, Biogen MA Inc, Celgene Corporation, Celgene International II Sarl, Genentech Inc, Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline, Sanofi, Maze Therapeutics Inc., Janssen Biotech Inc). Following biobanks are acknowledged for collecting the FinnGen project samples: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research\_and\_development/Finnish\_Clinical\_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta) and Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi).
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