Somatic mutations in chronic lung disease are associated with reduced lung function

Among human organs, the lung harbors one of the highest rates of somatic mutations. However, the relationship of these mutations to lung disease and function is not known. We analyzed the somatic mutational pattern from 1,251 samples of normal and diseased non-cancerous lung tissue from the Lung Tissue Research Consortium using RNA-seq. In two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD, 29%) and idiopathic pulmonary fibrosis (IPF, 13%), we found a significantly increased burden of somatic mutations compared to normal. Using deconvoluted cell type proportions, we found that a major predictor of somatic mutations was the airway to alveolar cell proportion and pathogenic cell types. We also found that mutational burden was associated with reduced lung function. This relationship remained even after adjustment for age, sex, smoking, and cell type proportion and in COPD and IPF. Our identification of an increased prevalence of somatic mutation in diseased lung that correlates with cell type proportion and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics. ### Competing Interest Statement Within the past 3 years JHY has received consulting fees from Bridge Biotherapeutics, institutional grant support from Bayer, AG has received consulting fees from TDA Research Inc, PJM has received consulting fees from foundation medicine, PJC has received institutional grant support from Bayer, AHL has received research funding from Three Lakes Foundation, CPH has received institutional grant supports from Alpha 1 Foundation, Bayer, Boerhinger-Ingelheim and Vertex, and has received consulting fees from Astra-Zeneka, Takeda and Sanofi. KB has received consulting fees from Cumberland Pharma, Novartis and Shionogi, served on External Science Advisory Board for AbbVie, Astra Zeneka, Dispersol, Eleven P15, Huitai Biomedicine, Redx Pharma and served as Scientific Advisory Board for Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, DevPro BioPharma, Galapagos NV, Galecto, Open Source Imaging Consortium, Pliant, Sanofi and Trevi Therapeutics and participated on Data Safety Monnitoring Board for Biogen, Humanetics, and Scleroderma Research Foundation. EKS has received institutional grant support from Bayer, MHC has received institutional grant support from Bayer. AGB is a paid advisor and holds equity in TenSixteen Bio. ### Funding Statement JHY is supported by NIH grant K08HL146972 and Eleanor and Miles Shore Faculty Development Awards Program. MHC is supported by NIH grant R01HL153248, R01HL149861, R01HL147148. AGB is supported by NIH grant DP5 OD029586, a Burroughs Wellcome Fund Career Award for Medical Scientists, and a Pew-Stewart Scholar for Cancer Research award, supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust. ### Author Declarations 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: IRB of Mass General Brigham gave ethical approval for this work. 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 Data are available on the NCBI database of Genotypes and Phenotypes (dbGaP), accession phs001662