Rare and Common Variants in <i>KIF15</i> Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis

Genetic studies of Idiopathic Pulmonary Fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified.To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis.We performed gene burden analysis of whole exome data, tested single variants for disease association, conducted KIF15 functional studies, and examined human lung single cell RNA sequencing data.Gene burden analysis of 1,725 cases and 23,509 controls identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT, RTEL1, PARN). KIF15 was implicated in autosomal dominant models of rare deleterious variants (OR 4.9 [95%CI 2.7, 8.8] P=2.55x10-7) and rare protein-truncating variants (OR 7.6 [3.3, 17.1], P=8.12x10-7). Meta-analysis of the discovery and replication cohorts, including 2,966 cases and 29,817 controls, confirm the involvement of KIF15, plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405, OR 1.6 [1.4, 1.9], P=5.63x10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells, and shows diminished expression in replicating epithelial cells of IPF patients.Both rare deleterious variants and common variants in KIF15 link a non-telomerase pathway of cell proliferation with IPF susceptibility.