Age-dependent Genetic Risk in Pulmonary Fibrosis Patients and Relatives

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is an age-related disorder with common and rare genetic risk factors. It is unknown if the effects of PF genetic risk factors differ by chronologic age. Objectives To assess age-specific effects of genetic risk factors in PF patients and their relatives. Methods We identified common and rare genetic risk factors using a Columbia whole genome sequencing (WGS) cohort (777 IPF, 2905 controls) and replicated findings using Trans-Omics for Precision Medicine (TOPMed, 1148 IPF, 5202 controls). We assessed age-stratified genetic risk of IPF and assessed for interaction with age across a range of cutoffs. We analyzed 313 FPF pedigrees and compared age-specific prevalence of interstitial lung disease in relatives stratified by proband genetic risk factors. Measurements and Main Results Adjusted odds of disease from MUC5B SNP increase with age, while odds of disease from rare variants decrease with age. The magnitude of the interaction term between age and both genetic variables was greatest in younger individuals. There were significant interactions between age