Background Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex. Aim To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery. Methods We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes. Results We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals included MUC1, which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, and NTN4 encoding Netrin-4 whose known roles include angiogenesis. The third signal may map to SLC6A6, a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction. Conclusion Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles of MUC1 and of endothelial cell and vascular changes in IPF.

LD is full-time employee of Genentech. AS hold stock options in Genentech. MN is full time employee of Genentech, Inc., a wholly owned subsidiary of Roche, and from which entity the data was sourced without fee/requirement. XRS, MM and BLY are full-time employees of Genentech and hold stock options in Roche. WAF is full-time employee of GSK. JMO reports personal fees from Boehringer Ingelheim, Genentech, United Therapeutics, AmMax Bio and Lupin Pharmaceuticals outside of the submitted work. DAS is a consultant for Vertex and the founder and chief scientific officer of Eleven P15, a company focused on the early detection and treatment of pulmonary fibrosis. BG has received in-kind research support from Galecto Biotech, and consultancy honoraria from GSK. AA reports personal fees from Boehringer Ingelheim, Genentech, Medscape, Abbvie, PatientMpower, Brainomix, PureTech, Gossamer Bio and Inogen outside of the submitted work. MES reports research funding from Boehringer Ingelheim, consultancy for Boehringer Ingelheim, and participation on Adjudication Committee or Data Safety Board for Bristol Myers Squibb, Fibrinogen and Pliant. SH reports payment from Trevi therapeutics, Boehringer Ingelheim, and Chiesi. SJ reports payment from Boehringer Ingelheim. TMM reports personal fees from Boehringer Ingelheim, Roche/Genentech, Abbvie, Amgen, Astra Zeneca, Bayer, Bridge bio, Bristol-Myers Squibb, CSL Behring, Galapagos, Galecto, GSK, IQVIA, Merck, Pfizer, Pliant, PureTech, Sanofi, Trevi, Vicore; and participation in Fibrogen, United Therapeutics and Nerre. IN reports personal fees from Boehringer Ingelheim and Sanofi. HP reports personal fees from Boehringher Ingelheim Ltd and Trevi Therapeutics. PLM reports advisory board fees from Hoffman-La Roche, Boehringer Ingelheim, AstraZeneca, Trevi, Qureight, Endevour; and personal fees from United Therapeutics. MDT reports respiratory Drug Delivery 2023 speaker fee, unrelated to the manuscript. MM-M reports payment from Boehringer Ing, Ferrer, and Chiesi. FM reports consulting but no fees from AstraZeneca, Boehringer Ingelheim, Excalibur, GSK, Hoffmann-LaRoche, Lung Therapeutics, RS Biotherapeutics, Two XR; and travel expenses paid by Boehringer Ingelheim. CF declares funding Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III and Instituto Tecnologico y de Energias Renovables; honoraria in educational events from Fundacion Instituto Roche. RGJ reports honoraria from Chiesi, Roche, PatientMPower, AstraZeneca, GSK, Boehringer Ingelheim, and consulting fees from AdAlta, Abbvie, Arda Therapeutics, Bristol Myers Squibb, Veracyte, RedX, Pliant, Chiesi. LVW reports research funding from GlaxoSmithKline, Roche and Orion Pharma, and consultancy for GlaxoSmithKline and Galapagos, outside of the submitted work. The other authors declare no competing interests.

This study was funded by a Medical Research Council Programme Grant (MR/V00235X/1) to RGJ and LVW by a Wellcome Trust PhD studentship for DC as part of the Wellcome Trust Genetic Epidemiology and Public Health Genomics Doctoral Training Programme (218505/Z/19/Z). LVW held a GlaxoSmithKline / Asthma + Lung UK Chair in Respiratory Research (C17-1). BGG is supported by Wellcome Trust grant 221680/Z/20/Z. JMO reports National Institutes of Health (NIH) National Heart, Lung, and Blood Institute grants R56HL158935 and K23HL138190. CF is supported by the Instituto de Salud Carlos III (PI20/00876, PI23/00980, CB06/06/1088, and PMP22/00083), co-financed by the European Regional Development Funds "A way of making Europe" from the EU, and by an agreement with Instituto Tecnologico y de Energias Renovables (ITER) to strengthen scientific and technological education, training, research, development and innovation in genomics, epidemiological surveillance based on massive sequencing, personalized medicine, and biotechnology (OA23/043). CJR was supported by Wellcome grant 201291/Z/16/Z. This work was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. This research used the ALICE and SPECTRE High Performance Computing Facility at the University of Leicester. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This research was conducted with appropriate ethics approval. The PROFILE study (which provided samples for the UK and UUS studies) had institutional ethics approval at the University of Nottingham (NCT01134822 - ethics reference 10/H0402/2) and Royal Brompton and Harefield NHS Foundation Trust (NCT01110694 - ethics reference 10/H0720/12). UK samples were recruited across multiple sites with individual ethics approval (University of Edinburgh Research Ethics Committee [The Edinburgh Lung Fibrosis Molecular Endotyping (ELFMEN) Study NCT04016181] 17/ES/0075, NRES Committee South West - Southmead, Yorkshire and Humber Research Ethics Committee 08/H1304/54 and Nottingham Research Ethics Committee 09/H0403/59). Spanish samples were recruited under ethics approval by ethics committee from the Hospital Universitario N.S. de Candelaria (reference of the approval: PI-19/12). The UUS study also included individuals from clinical trials with ethics approval (ACE [NCT00957242] and PANTHER [NCT00650091]). For the UCSF cohort, sample and data collection were approved by the University of California San Francisco Committee on Human Research and all patients provided written informed consent. For the Vanderbilt cohort, the Institutional Review Boards from Vanderbilt University approved the study and all participants provided written informed consent before enrolment. For individuals recruited at the University of Chicago, consenting patients with IPF who were prospectively enrolled in the institutional review board-approved ILD registry (IRB#14163A) were included. Individuals recruited at the University of Pittsburgh Medical Centre had ethics approval from the University of Pittsburgh Human Research Protection Office (referenceSTUDY20030223: Genetic Polymorphisms in IPF). Individuals from the COMET (NCT01071707) and Lung Tissue Research Consortium (NCT02988388) studies were also included in the Chicago study. All subjects in the Colorado study gave written informed consent as part of IRB-approved protocols for their recruitment at each site and the GWAS study was approved by the National Jewish Health IRB and Colorado Combined Institutional Review Boards (COMIRB). Subjects in the Genentech study provided written informed consent for whole-genome sequencing of their DNA. Ethical approval was provided as per the original clinical trials (INSPIRE [NCT00075998], RIFF [NCT01872689], CAPACITY [NCT00287729 and NCT00287716] and ASCEND [NCT01366209]). Individuals in the CleanUP-UCD study included individuals from clinical trials with ethics approval (NCT02759120). These samples were genotyped under University of Virginia ethics approval (IRB 20845). IPFJES involved human participants and was approved by East Midlands - Nottingham 1 Research Ethics Committee REC reference: 17/EM/0021IRAS project ID: 203355. Participants gave informed consent to participate in the study before taking part.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Summary statistics (i.e., effect size estimates, standard errors, p values and basic variant information) for all variants included in the genome-wide meta-analysis can be accessed via https://github.com/genomicsITER/PFgenetics.

https://github.com/genomicsITER/PFgenetics