Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Sin, Don D; O'Connor, George T; Newell Jr., John D; Allen, Richard J; Guillen-Guio, Beatriz; Oldham, Justin M; Ma, Shwu Fan; Dressen, Amy; Paynton, Megan L; Kraven, Luke M; Obeidat, Ma'en; Li, Xuan; Ng, Michael; Braybrooke, Rebecca; Molina-Molina, Maria; Hobbs, Brian D; Putman, Rachel K; Sakornsakolpat, Phuwanat; Booth, Helen L.; Fahy, William A; Hart, Simon P; Hill, Mike R; Hirani, Nik; Hubbard, Richard B.; McAnulty, Robin J; Millar, Ann B; Navaratnam, Vidyia; Oballa, Eunice; Parfrey, Helen; Saini, Gauri; Whyte, Moira K. B.; Zhang, Yingze; Kaminski, Naftali; Adegunsoye, Ayodeji; Strek, Mary E.; Neighbors, Margaret; Sheng, Xuting R.; Gudmundsson, Gunnar; Gudnason, Vilmundur; Hatabu, Hiroto; Lederer, David J; Manichaikul, Ani; Newell, Jr., John D.; O'Connor, George T.; Ortega, Victor E; Xu, Hanfei; Fingerlin, Tasha E; Bossé, Yohan; Hao, Ke; Joubert, Philippe; Nickle, David C; Sin, Don D.; Timens, Wim; Furniss, Dominic; Morris, Andrew P; Zondervan, Krina; Hall, Ian P.; Sayers, Ian; Tobin...

Abstract

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 threenewgenome-wide significant (P

Citation

Sin, D. D., O'Connor, G. T., Newell Jr., J. D., Allen, R. J., Guillen-Guio, B., Oldham, J. M., Ma, S. F., Dressen, A., Paynton, M. L., Kraven, L. M., Obeidat, M., Li, X., Ng, M., Braybrooke, R., Molina-Molina, M., Hobbs, B. D., Putman, R. K., Sakornsakolpat, P., Booth, H. L., Fahy, W. A., …Wain, L. V. (2020). Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 201(5), 564-574. https://doi.org/10.1164/rccm.201905-1017OC

• Journal Article Type: Article
• Acceptance Date: Nov 7, 2019
• Online Publication Date: Nov 11, 2019
• Publication Date: Mar 1, 2020
• Deposit Date: Nov 13, 2019
• Publicly Available Date: Nov 19, 2019
• Journal: American Journal of Respiratory and Critical Care Medicine
• Print ISSN: 1073-449X
• Publisher: American Thoracic Society
• Peer Reviewed: Peer Reviewed
• Volume: 201
• Issue: 5
• Pages: 564-574
• DOI: https://doi.org/10.1164/rccm.201905-1017OC
• Keywords: Genetics; Epidemiology; KIF15; MAD1L1; DEPTOR
• Public URL: https://hull-repository.worktribe.com/output/3156921
• Publisher URL: https://www.atsjournals.org/doi/abs/10.1164/rccm.201905-1017OC
• Contract Date: Nov 18, 2019