Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.
Allen RJ., Guillen-Guio B., Oldham JM., Ma S-F., Dressen A., Paynton ML., Kraven LM., Obeidat M., Li X., Ng M., Braybrooke R., Molina-Molina M., Hobbs BD., Putman RK., Sakornsakolpat P., Booth HL., Fahy WA., Hart SP., Hill MR., Hirani N., Hubbard RB., McAnulty RJ., Millar AB., Navaratnam V., Oballa E., Parfrey H., Saini G., Whyte MKB., Zhang Y., Kaminski N., Adegunsoye A., Strek ME., Neighbors M., Sheng XR., Gudmundsson G., Gudnason V., Hatabu H., Lederer DJ., Manichaikul A., Newell JD., O'Connor GT., Ortega VE., Xu H., Fingerlin TE., Bossé Y., Hao K., Joubert P., Nickle DC., Sin DD., Timens W., Furniss D., Morris AP., Zondervan KT., Hall IP., Sayers I., Tobin MD., Maher TM., Cho MH., Hunninghake GM., Schwartz DA., Yaspan BL., Molyneaux PL., Flores C., Noth I., Jenkins RG., Wain LV.
Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P