ABSTRACT Unbiased genomic approaches have led to discoveries of novel disease genes and variants. Most pathogenic rare variants found in patients with Familial Pulmonary Fibrosis (FPF) and Idiopathic Pulmonary Fibrosis (IPF) result in telomere shortening. Thus, these diseases are part of the spectrum of diseases known as telomeropathies or short telomere syndromes. Telomere lengths of peripheral blood cells predict clinical outcomes of IPF patients, including survival, rate of disease progression, and response to certain medications. A larger proportion of FPF and IPF patients have evidence of telomere shortening than are explained by genetic mutations. This study seeks to use whole genome sequencing to identify genetic variants that engender an inherited susceptibility to lung fibrosis. The underlying hypothesis of this application is that telomerase dysfunction is a key mechanism underlying development of pulmonary fibrosis. This application plans to evaluate whole genome sequence (WGS) data obtained for a discovery cohort of ~950 unrelated FPF probands and IPF patients. In Aim 1, we will estimate telomere length from the WGS data, identify rare coding and noncoding qualifying variants in the telomere genes, assess genotype-phenotype relationships, and study the return of genetic results to patients and their physicians. This aim will allow for assessment of known telomere genes in well-phenotyped patients. Since a large portion of FPF and IPF patients with telomere lengths <10th percentile have no identifiable telomere-related pathogenic or likely pathogenic variant, we will utilize WGS data and five independent strategies to identify novel candidate genes: analysis of variants by genomic location, analysis of rare variants by gene-based collapsing tests, analysis of common variants by GWAS, analysis of variants using a sliding window test, and analysis of copy number variants. Candidate genes and variants identified in the discovery cohort will be evaluated in replicate cohorts. This aim has the potential to discover new genes linked to pulmonary fibrosis and telomere biology. In Aim 3, we will explore three avenues of functional investigation: through assessment of co-segregation in informative kindreds, through in vitro studies of gene function in patient-derived lymphocytes and other cell types, and through evaluation of CRISPR/Cas9-engineered mouse models of disease. The latter aim will focus on elucidating the function of PARN, a de-adenylase that has an important role in the post-transcriptional maturation of telomerase RNA, with regard to the development of pulmonary fibrosis. Overall, this application plans to use WGS, large FPF and IPF cohorts, as well as cutting-edge statistical analyses and experimental approaches to extend our knowledge of the genetic architecture of pulmonary fibrosis and human telomere- related diseases.