Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Anna L Peljto, Rachel Z Blumhagen, Avram D Walts, Jonathan Cardwell, Julia Powers, Tamera J Corte, Joanne L Dickinson, Ian Glaspole, Yuben P Moodley, Martina Koziar Vasakova, Elisabeth Bendstrup, Jesper R Davidsen, Raphael Borie, Bruno Crestani, Philippe Dieude, Francesco Bonella, Ulrich Costabel, Gunnar Gudmundsson, Seamas C DonnellyJim Egan, Michael T Henry, Michael P Keane, Marcus P Kennedy, Cormac McCarthy, Aoife N McElroy, Joshua A Olaniyi, Katherine M A O'Reilly, Luca Richeldi, Paolo M Leone, Venerino Poletti, Francesco Puppo, Sara Tomassetti, Valentina Luzzi, Nurdan Kokturk, Nesrin Mogulkoc, Christine A Fiddler, Nikhil Hirani, Gisli Jenkins, Toby M Maher, Philip L Molyneaux, Helen Parfrey, Rebecca Braybrooke, Timothy S Blackwell, Peter D Jackson, Steven D Nathan, Mary K Porteous, Kevin K Brown, Jason D Christie, Harold R Collard, Oliver Eickelberg, Elena E Foster, Kevin F Gibson, Marilyn Glassberg, Daniel Kass, Jonathan A Kropski, David Lederer, Angela L Linderholm, Jim Loyd, Susan K Mathai, Sydney B Montesi, Imre Noth, Justin M Oldham, Amy J Palmisciano, Cristina A Reichner, Mauricio Rojas, Jesse Roman, Neil Schluger, Barry S Shea, Jeffrey J Swigris, Paul J Wolters, Yingze Zhang, Cecilia M A Prele, Juan I Enghelmayer, Maria Otaola, Christopher J Ryerson, Mauricio Salinas, Martina Sterclova, Tewodros H Gebremariam, Marjukka Myllärniemi, Roberto Carbone, Haruhiko Furusawa, Masaki Hirose, Yoshikazu Inoue, Yasunari Miyazaki, Ken Ohta, Shin Ohta, Tsukasa Okamoto, Dong Soon Kim, Annie Pardo, Moises Selman, Alvaro U Aranda, Moo Suk Park, Jong Sun Park, Jin Woo Song, Maria Molina-Molina, Lurdes Planas-Cerezales, Gunilla Westergren-Thorsson, Albert V Smith, Ani W Manichaikul, John S Kim, Stephen S Rich, Elizabeth C Oelsner, R Graham Barr, Jerome I Rotter, Josee Dupuis, George O'Connor, Ramachandran S Vasan, Michael H Cho, Edwin K Silverman, Marvin I Schwarz, Mark P Steele, Joyce S Lee, Ivana V Yang, Tasha E Fingerlin, David A Schwartz

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

RATIONALE: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic 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 variants that are influential within genes and estimated the heritability of IPF based on 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% (s.e. 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 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.

Original languageEnglish
Pages (from-to)1194-1202
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume207
Issue number9
Early online date5 Jan 2023
DOIs
Publication statusPublished - 1 May 2023

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