Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants
Anna L. Peljto, Rachel Z. Blumhagen, Avram Walts, Jonathan Cardwell, Julia Powers, Tamera J. Corte, Joanne L. Dickinson, Ian Glaspole, Yuben Moodley, Martina Vašáková, Elisabeth Bendstrup, Jesper Rømhild Davidsen, Raphaël Borie, Bruno Crestani, Philippe Dieudé, Francesco Bonella, Ulrich Costabel, Gunnar Guðmundsson, Seamas C. Donnelly, Jim Egan, Michael T. Henry, Michael P. Keane, Marcus P. Kennedy, Cormac McCarthy, Aoife McElroy, Joshua A. Olaniyi, Katherine Ma O’Reilly, Luca Richeldi, Paolo Maria Leone, Venerino Poletti, Francesco Puppo, Sara Tomassetti, Valentina Luzzi, Nurdan Köktürk, Nesrin Moğulkoç, Christine Fiddler, Nikhil Hirani, Gísli Jenkins, Toby M. Maher, Philip L. Molyneaux, Helen Parfrey, Rebecca Braybrooke, Timothy S. Blackwell, Peter Jackson, Steven D. Nathan, Mary K. Porteous, Kevin K. Brown, Jason D. Christie, Harold R. Collard, Oliver Eickelberg, Elena Foster, Kevin F. Gibson, Marilyn K. Glassberg, Daniel J. Kass, Jonathan A. Kropski, David J. Lederer, A. Linderholm, Jim Loyd, Susan Mathai, Sydney B. Montesi, Imre Noth, Justin M. Oldham, Amy Palmisciano, Cristina Reichner, Mauricio Rojas, Jesse Roman, Neil W. Schluger, Barry S. Shea, Jeffrey J. Swigris, Paul J. Wolters, Yingze Zhang, Cecilia M. Prêle, Juan Ignacio Enghelmayer, María Otaola, Christopher J. Ryerson, Mauricio Salinas, Martina Šterclová, Tewodros Haile Gebremariam, Marjukka Myllärniemi, Roberto G. Carbone, Haruhiko Furusawa, Masaki Hirose, Yoshikazu Inoue, Yasunari Miyazaki, Ken Ohta, Shin Ohta, Tsukasa Okamoto, Dong Soon Kim, Annie Pardo, Moisés Selman, Alvaro U. Aranda, Moo Suk Park, Jong Sun Park, Jin Woo Song, María Molina‐Molina, Lurdes Planas‐Cerezales, Gunilla Westergren‐Thorsson, Albert V. Smith, Ani Manichaikul, John S. Kim
Abstract
Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.