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

• DOI: 10.1038/s42003-021-01910-y
• Publication Date: 2021-03-23T11:04:44Z
• Authors: Ryan S. Dhindsa; Johan Mattsson; Abhishek Nag; Quanli Wang; Louise V. Wain; Richard Allen; Eleanor M. Wigmore; Kristina Ibanez; Dimitrios Vitsios; Sri V. V. Deevi; Sebastian Wasilewski; Maria Karlsson; Glenda Lassi; Henric Olsson; Daniel Muthas; Susan Monkley; Alex Mackay; Lynne Murray; Simon Young; Carolina Haefliger; ; Toby M. Maher; Maria G. Belvisi; Gisli Jenkins; Philip L. Molyneaux; Adam Platt; Slavé Petrovski
• Keywords: Life Sciences & Biomedicine - Other Topics; Male; 0301 basic medicine; QH301-705.5; FinnGen Consortium; Mutation, Missense; 610; Cell Cycle Proteins; Article; 03 medical and health sciences; Exome Sequencing; Humans; Genetic Predisposition to Disease; Biology (General); Biology; Aged; Science & Technology; Idiopathic Pulmonary Fibrosis; 3. Good health; Multidisciplinary Sciences; Phenotype; Case-Control Studies; Science & Technology - Other Topics; Female; Life Sciences & Biomedicine; Genome-Wide Association Study

AbstractIdiopathic 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.