title: An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology.
  
  
  
  The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis.
  
  
  
  We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis.
  
  
  
  We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10-7) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10-22).
  
  
  
  We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.
authors.affiliation: 1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.|2 Department of Medicine, Austin Health and Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Slavé
authors.identifier: 0000-0002-1527-961X
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.|4 Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Todd
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.|4 Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Michael T
authors.identifier: 0000-0002-4186-5698
authors.initials: MT
authors.lastname: Durheim
authors.affiliation: 1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Quanli
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 5 Gilead Sciences, Foster City, California.
authors.forename: Jason W
authors.identifier: 0000-0003-4695-2923
authors.initials: JW
authors.lastname: Chien
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Fran L
authors.initials: FL
authors.lastname: Kelly
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Courtney
authors.initials: C
authors.lastname: Frankel
authors.affiliation: 1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Mebane
authors.affiliation: 1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ren
authors.affiliation: 1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Joshua
authors.initials: J
authors.lastname: Bridgers
authors.affiliation: 6 Division of Pharmacotherapy and Experimental Therapeutics, Center for Pharmacogenomics and Individualized Therapy, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.affiliation: 1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Malone
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ashley
authors.initials: A
authors.lastname: Finlen Copeland
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Christie
authors.initials: C
authors.lastname: Brinkley
authors.affiliation: 7 Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Andrew S
authors.identifier: 0000-0002-7232-2143
authors.initials: AS
authors.lastname: Allen
authors.affiliation: 5 Gilead Sciences, Foster City, California.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Riordan
authors.affiliation: 5 Gilead Sciences, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.|4 Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
authors.affiliation: 1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged
keywords: collapsing analysis; exome sequencing; genetics; interstitial lung disease; pulmonary fibrosis