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.

Allergy Asthma and Clinical Immunology Clinic Alfred Health Sydney Australia

Asan Medical Center University of Ulsan Seoul Republic of Korea

Baylor University Medical Center Dallas Texas

Boston University and National Heart Lung and Blood Institute Framingham Heart Study Boston Massachusetts; and

Brown University Providence Rhode Island

Cardiopulmonary Research Center Alliance Pulmonary Group Guaynabo Puerto Rico

Center for Interstitial and Rare Lung Diseases Ruhrlandklinik University Hospital University of Duisburg Essen Essen Germany

Center for Public Health Genomics and

Center for Rare Lung Diseases Department of Respiratory Diseases and Allergy Aarhus University Hospital Aarhus Denmark

Channing Division of Network Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts

College of Health Sciences Addis Ababa University Addis Ababa Ethiopia

Columbia University Medical Center New York New York

Departamento de Medicina Universidad de Chile Santiago Chile

Department of Biostatistics School of Public Health Boston University Boston Massachusetts

Department of Biostatistics School of Public Health University of Michigan Ann Arbor Michigan

Department of Clinical and Experimental Medicine Interventional Pulmonology Unit Careggi University Hospital Florence Italy

Department of Clinical Medicine Aarhus University Aarhus Denmark

Department of Diseases of the Thorax G B Morgagni Hospital Forlì Italy

Department of Epidemiology Biostatistics and Occupational Health McGill University Montréal Quebec Canada

Department of Experimental Medical Science Lung Biology Unit Lund University Lund Sweden

Department of Internal Medicine University of California Davis Davis California

Department of Internal Medicine University of Genoa Genoa Italy

Department of Medical and Surgical Sciences DIMES University of Bologna Bologna Italy

Department of Medicine

Department of Medicine and

Department of Medicine and Department of Epidemiology Columbia University Medical Center New York New York

Department of Medicine Showa University Tokyo Japan

Department of Medicine University of British Columbia Vancouver British Columbia Canada

Department of Medicine University of Colorado Anschutz Medical Campus Aurora Colorado

Department of Public Health Sciences University of Virginia Charlottesville Virginia

Department of Pulmonary and Critical Care Medicine Virginia Commonwealth University Richmond Virginia

Department of Pulmonary Medicine Heart and Lung Center Helsinki University Hospital Helsinki Finland

Department of Pulmonology Ege University Hospital Izmir Turkey

Department of Respiratory Medicine and Sleep Landspitali University Hospital Reykjavik Iceland

Department of Respiratory Medicine Cork University Hospital Cork Ireland

Department of Respiratory Medicine Tokyo Medical and Dental University Tokyo Japan

Department of Respiratory Medicine University of Western Australia Perth Australia

Department of Respiratory Medicine University Thomayer Hospital Prague Czech Republic

Division of Pulmonary Allergy and Critical Care Medicine Department of Medicine University of Pittsburgh Pittsburgh Pennsylvania

Division of Pulmonary Allergy and Critical Care Thomas Jefferson University Philadelphia Pennsylvania

Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts

Division of Pulmonary Critical Care Allergy and Sleep Medicine Department of Medicine University of California San Francisco San Francisco California

Division of Pulmonary Critical Care and Sleep Medicine Alpert Medical School Brown University Providence Rhode Island

Division of Pulmonary Critical Care and Sleep Medicine College of Medicine University of Arizona Phoenix Arizona

Division of Pulmonary Critical Care and Sleep Medicine MedStar Georgetown University Hospital Washington DC

Division of Pulmonary Critical Care and Sleep Medicine Ohio State University Columbus Ohio

Division of Pulmonary Critical Care and Sleep Medicine School of Medicine University of California Davis Sacramento California

Division of Respiratory Medicine University of Nottingham Nottingham United Kingdom

Faculty of Medicine Gazi University Ankara Turkey

Faculty of Medicine University of Iceland Reykjavik Iceland

Faculty of Sciences Universidad Nacional Autónoma de México Mexico City Mexico

Fondazione Policlinico A Gemelli IRCCS Rome Italy

Hospital de Clínicas Universidad de Buenos Aires Buenos Aires Argentina

Hospital of the University of Pennsylvania Philadelphia Pennsylvania

Inova Fairfax Hospital Falls Church Virginia

Institute for Respiratory Health University of Western Australia Perth Australia

Instituto de Rehabilitación Psicofísica de Buenos Aires Buenos Aires Argentina

Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas Mexico City Mexico

Interstitial Lung Disease Multidisciplinary Unit University Hospital of Bellvitge University of Barcelona Barcelona Spain

Interventional Pulmonology Unit Careggi University Hospital Florence Italy

Keck Medicine of USC University of Southern California Los Angeles California

Mater Misericordiae University Hospital Dublin Ireland

Menzies Institute of Medical Research University of Tasmania Hobart Tasmania Australia

National Heart and Lung Institute Imperial College London London United Kingdom

National Hospital Organization Kinki Chuo Chest Medical Center Osaka Japan

National Hospital Organization Tokyo National Hospital Tokyo Japan

National Jewish Health Denver Colorado

National Lung Transplantation Centre Mater Misericordiae University Hospital Dublin Ireland

Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania

Pulmonary Center School of Medicine Boston University Boston Massachusetts

Regeneron Pharmaceuticals Inc Tarrytown New York

Respiratory Department and

Royal Papworth Hospital NHS Foundation Trust Cambridge United Kingdom

Royal Prince Alfred Hospital University of Sydney Sydney Australia

Seoul National University Bundang Hospital Seoul National University Seongnam Republic of Korea

Service de Pneumologie A and

Service de Rhumatologie Hopital Bichat Paris France

Severance Hospital Yonsei University College of Medicine Seoul Republic of Korea

South Danish Center for Interstitial Lung Diseases Department of Respiratory Medicine Odense University Hospital Odense Denmark

St Vincent's University Hospital University College Dublin Dublin Ireland

The Institute for Translational Genomics and Population Sciences Department of Pediatrics The Lundquist Institute at Harbor UCLA Medical Center Torrance California

Trinity College Dublin Dublin Ireland

Università Cattolica del Sacro Cuore Rome Italy

Université Paris Cité INSERM Physiopathologie et Épidémiologie des Maladies Respiratoires Paris France

University of Edinburgh Edinburgh United Kingdom

Vanderbilt University Medical Center Nashville Tennessee

Komentář v

Am J Respir Crit Care Med. 2023 May 1;207(9):1118-1120. doi: 10.1164/rccm.202301-0177ED. PubMed

Erratum v

Am J Respir Crit Care Med. 2024 Feb 15;209(4):462. doi: 10.1164/rccm.v209erratum2. PubMed

Zobrazit více v PubMed

Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med . 2018;198:e44–e68. PubMed

Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med . 2018;379:797–798. PubMed

Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis . 2008;3:8. PubMed PMC

Baumgartner KB, Samet JM, Coultas DB, Stidley CA, Hunt WC, Colby TV, et al. Collaborating Centers Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Am J Epidemiol . 2000;152:307–315. PubMed

Pinheiro GA, Antao VC, Wood JM, Wassell JT. Occupational risks for idiopathic pulmonary fibrosis mortality in the United States. Int J Occup Environ Health . 2008;14:117–123. PubMed

Helling BA, Gerber AN, Kadiyala V, Sasse SK, Pedersen BS, Sparks L, et al. Regulation of MUC5B expression in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol . 2017;57:91–99. PubMed PMC

Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med . 2011;364:1503–1512. PubMed PMC

Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele MP, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet . 2013;45:613–620. PubMed PMC

Mushiroda T, Wattanapokayakit S, Takahashi A, Nukiwa T, Kudoh S, Ogura T, et al. Pirfenidone Clinical Study Group A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis. J Med Genet . 2008;45:654–656. PubMed

Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med . 2013;1:309–317. PubMed PMC

Fingerlin TE, Zhang W, Yang IV, Ainsworth HC, Russell PH, Blumhagen RZ, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet . 2016;17:74. PubMed PMC

Allen RJ, Porte J, Braybrooke R, Flores C, Fingerlin TE, Oldham JM, et al. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study. Lancet Respir Med . 2017;5:869–880. PubMed PMC

Moore C, Blumhagen RZ, Yang IV, Walts A, Powers J, Walker T, et al. Resequencing study confirms that host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med . 2019;200:199–208. PubMed PMC

Allen RJ, Guillen-Guio B, Oldham JM, Ma SF, Dressen A, Paynton ML, et al. Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. Am J Respir Crit Care Med . 2020;201:564–574. PubMed PMC

Zhang D, Povysil G, Kobeissy PH, Li Q, Wang B, Amelotte M, et al. Rare and common variants in KIF15 contribute to genetic risk of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med . 2022;206:56–69. PubMed PMC

Nogee LM, Dunbar AE, III, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med . 2001;344:573–579. PubMed

Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med . 2007;356:1317–1326. PubMed

Lawson WE, Grant SW, Ambrosini V, Womble KE, Dawson EP, Lane KB, et al. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax . 2004;59:977–980. PubMed PMC

Thomas AQ, Lane K, Phillips J, III, Prince M, Markin C, Speer M, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med . 2002;165:1322–1328. PubMed

Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA . 2007;104:7552–7557. PubMed PMC

van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, et al. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort. Am J Respir Crit Care Med . 2010;182:1419–1425. PubMed

Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet . 2009;84:52–59. PubMed PMC

Stuart BD, Choi J, Zaidi S, Xing C, Holohan B, Chen R, et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet . 2015;47:512–517. PubMed PMC

Coghlan MA, Shifren A, Huang HJ, Russell TD, Mitra RD, Zhang Q, et al. Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations. BMJ Open Respir Res . 2014;1:e000057. PubMed PMC

Cogan JD, Kropski JA, Zhao M, Mitchell DB, Rives L, Markin C, et al. Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med . 2015;191:646–655. PubMed PMC

Petrovski S, Todd JL, Durheim MT, Wang Q, Chien JW, Kelly FL, et al. An exome sequencing study to assess the role of rare genetic variation in pulmonary fibrosis. Am J Respir Crit Care Med . 2017;196:82–93. PubMed PMC

Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature . 2021;590:290–299. PubMed PMC

Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, et al. NHLBI GO Exome Sequencing Project—ESP Lung Project Team Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet . 2012;91:224–237. PubMed PMC

Loehlein Fier H, Prokopenko D, Hecker J, Cho MH, Silverman EK, Weiss ST, et al. On the association analysis of genome-sequencing data: a spatial clustering approach for partitioning the entire genome into nonoverlapping windows. Genet Epidemiol . 2017;41:332–340. PubMed PMC

Blumhagen RZ, Schwartz DA, Langefeld CD, Fingerlin TE. Identification of influential variants in significant aggregate rare variant tests. Hum Hered . 2021 doi: 10.1159/000513290. PubMed DOI PMC

Yang J, Bakshi A, Zhu Z, Hemani G, Vinkhuyzen AA, Lee SH, et al. LifeLines Cohort Study Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat Genet . 2015;47:1114–1120. PubMed PMC

Dhindsa RS, Mattsson J, Nag A, Wang Q, Wain LV, Allen R, et al. FinnGen Consortium Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis. Commun Biol . 2021;4:392. PubMed PMC

Allen RJ, Stockwell A, Oldham JM, Guillen-Guio B, Schwartz DA, Maher TM, et al. International IPF Genetics Consortium Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis. Thorax . 2022;77:829–833. PubMed PMC

Dressen A, Abbas AR, Cabanski C, Reeder J, Ramalingam TR, Neighbors M, et al. Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study. Lancet Respir Med . 2018;6:603–614. PubMed PMC

Guillot L, Epaud R, Thouvenin G, Jonard L, Mohsni A, Couderc R, et al. New surfactant protein C gene mutations associated with diffuse lung disease. J Med Genet . 2009;46:490–494. PubMed

Legendre M, Butt A, Borie R, Debray MP, Bouvry D, Filhol-Blin E, et al. Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer. Eur Respir J . 2020;56:2002806. PubMed

Alder JK, Stanley SE, Wagner CL, Hamilton M, Hanumanthu VS, Armanios M. Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest . 2015;147:1361–1368. PubMed PMC

Campo I, Zorzetto M, Mariani F, Kadija Z, Morbini P, Dore R, et al. A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant. Respir Res . 2014;15:43. PubMed PMC

Mathai SK, Humphries S, Kropski JA, Blackwell TS, Powers J, Walts AD, et al. MUC5B variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis. Thorax . 2019;74:1131–1139. PubMed PMC

Hunninghake GM, Quesada-Arias LD, Carmichael NE, Martinez Manzano JM, Poli De Frías S, Baumgartner MA, et al. Interstitial lung disease in relatives of patients with pulmonary fibrosis. Am J Respir Crit Care Med . 2020;201:1240–1248. PubMed PMC

Putman RK, Gudmundsson G, Axelsson GT, Hida T, Honda O, Araki T, et al. Imaging patterns are associated with interstitial lung abnormality progression and mortality. Am J Respir Crit Care Med . 2019;200:175–183. PubMed PMC

Steele MP, Peljto AL, Mathai SK, Humphries S, Bang TJ, Oh A, et al. Incidence and progression of fibrotic lung disease in an at-risk cohort. Am J Respir Crit Care Med . 2023;207:587–593. PubMed PMC