Richard J. AllenBeatriz Guillen-GuioJustin M. OldhamShwu Fan MaAmy DressenMegan L. PayntonLuke M. KravenMa'en ObeidatXuan LiMichael NgRebecca BraybrookeMaria Molina-MolinaBrian D. HobbsRachel K. PutmanPhuwanat SakornsakolpatHelen L. BoothWilliam A. FahySimon P. HartMike R. HillNik HiraniRichard B. HubbardRobin J. McAnultyAnn B. MillarVidyia NavaratnamEunice OballaHelen ParfreyGauri SainiMoira K.B. WhyteYingze ZhangNaftali KaminskiAyodeji AdegunsoyeMary E. StrekMargaret NeighborsXuting R. ShengGunnar GudmundssonVilmundur GudnasonHiroto HatabuDavid J. LedererAni ManichaikulJohn D. NewellGeorge T. O'ConnorVictor E. OrtegaHanfei XuTasha E. FingerlinYohan BosséKe HaoPhilippe JoubertDavid C. NickleDon D. SinWim TimensDominic FurnissAndrew P. MorrisKrina T. ZondervanIan P. HallIan SayersMartin D. TobinM. TobyMichael H. ChoGary M. HunninghakeDavid A. SchwartzBrian L. YaspanPhilip L. MolyneauxCarlos FloresImre NothR. Gisli JenkinsLouise V. WainCentro de Investigación Biomédica en Red de Enfermedades RespiratoriasNational Jewish HealthWellcome Trust Centre for Human GeneticsInstitut universitaire de cardiologie et de pneumologie de Québec - Université LavalInstituto Tecnológico y de Energías Renovables, S.A.Landspitali University HospitalIcelandic Heart AssociationHaskoli IslandsPapworth Hospital, NHS Foundation TrustUniversity of LeicesterWake Forest School of MedicineThe University of ChicagoColumbia University Irving Medical CenterUniversity of EdinburghUniversity of OxfordGenentech IncorporatedInstitut d'Investigació Biomedica de BellvitgeCastle Hill HospitalNottingham University Hospitals NHS TrustFramingham Heart StudyUCLUniversity of VirginiaUniversity of LiverpoolUniversity of BristolGlaxoSmithKline plc.Boston UniversityYale School of MedicineBrigham and Women's HospitalUniversity of PittsburghUniversity of Washington, SeattleUniversity of NottinghamUniversity of California, DavisIcahn School of Medicine at Mount SinaiVagelos College of Physicians and SurgeonsFaculty of Medicine, Siriraj Hospital, Mahidol UniversityNational Heart and Lung InstituteThe University of British ColumbiaUniversity of Colorado at DenverUniversity of Iowa Carver College of MedicineGlenfield HospitalRoyal Brompton HospitalMerck &amp; Co., Inc.University of Groningen, University Medical Center GroningenUniversity of ManchesterUniversidad de la LagunaUniversitat de BarcelonaGroningen Research Institute for Asthma and COPDHospital Ntra2020-03-262020-03-262020-03-01American Journal of Respiratory and Critical Care Medicine. Vol.201, No.5 (2020), 564-574153549701073449X2-s2.0-85080088253https://repository.li.mahidol.ac.th/handle/20.500.14594/53750© 2020 by the American Thoracic Society. 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<5×10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.Mahidol UniversityMedicineArticleSCOPUS10.1164/rccm.201905-1017OC