RATIONALE:Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. OBJECTIVE:To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. METHODS:We performed deep targeted resequencing (3.69 Mb of DNA) in cases (N=3,624) and controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test. MEASUREMENTS AND MAIN RESULTS:Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant, rs35705950, with an OR of 5.45 (95% CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95% CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in risk of IPF in the TERT and RTEL1 gene regions, and found that the FAM13A and TERT regions have independent common and rare variant signals. CONCLUSIONS:A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions; these genetic variants focus on biological mechanisms of host defense and cell senescence.