{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T23:42:05Z","timestamp":1794440525256,"version":"4.9.1"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2021,2]]},"abstract":"\n Background:<\/jats:title>\n Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics.<\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource\u2014Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed.<\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (\n KDR<\/jats:italic>\n ) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense\n KDR<\/jats:italic>\n variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in\n KDR<\/jats:italic>\n . Four additional PAH cases with rare likely loss-of-function variants in\n KDR<\/jats:italic>\n were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n The Bayesian inference approach allowed us to independently validate\n KDR<\/jats:italic>\n , which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for\n KDR<\/jats:italic>\n being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circgen.120.003155","type":"journal-article","created":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T12:01:03Z","timestamp":1608033663000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Bayesian Inference Associates Rare\n KDR<\/i>\n Variants With Specific Phenotypes in Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6762-5342","authenticated-orcid":true,"given":"Emilia M.","family":"Swietlik","sequence":"first","affiliation":[{"name":"Department of Medicine (E.M.S., D.P., T.T., C.M.T., M.R.T., N.W.M., S. Gr\u00e4f), University of Cambridge."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Greene","sequence":"additional","affiliation":[{"name":"Department of Haematology (D.G., K.M., C.J.P., J.C.S., S. Gr\u00e4f), University of Cambridge."},{"name":"NIHR BioResource for Translational Research, Cambridge, United Kingdom (D.G., K.M., J.M.M., C.J.P., J.C.S., N.W.M., S. Gr\u00e4f)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (N.Z., C.C.L.W.), Columbia University, NY."},{"name":"Department of Systems Biology (N.Z., Y.S.), Columbia University, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karyn","family":"Megy","sequence":"additional","affiliation":[{"name":"Department of Haematology (D.G., K.M., C.J.P., J.C.S., S. Gr\u00e4f), University of Cambridge."},{"name":"NIHR BioResource for Translational Research, Cambridge, United Kingdom (D.G., K.M., J.M.M., C.J.P., J.C.S., N.W.M., S. Gr\u00e4f)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"Cogliano","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield (M.C., J.M.W., A.L., A.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smitha","family":"Rajaram","sequence":"additional","affiliation":[{"name":"Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom (S.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Pandya","sequence":"additional","affiliation":[{"name":"Department of Medicine (E.M.S., D.P., T.T., C.M.T., M.R.T., N.W.M., S. Gr\u00e4f), University of Cambridge."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6762-5342","authenticated-orcid":true,"given":"Tobias","family":"Tilly","sequence":"additional","affiliation":[{"name":"Department of Medicine (E.M.S., D.P., T.T., C.M.T., M.R.T., N.W.M., S. Gr\u00e4f), University of Cambridge."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9554-7679","authenticated-orcid":true,"given":"Katie A.","family":"Lutz","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center (K.A.L., M.W.P., A.W.C., W.C.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3521-4458","authenticated-orcid":true,"given":"Carrie C.L.","family":"Welch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (N.Z., C.C.L.W.), Columbia University, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Pauciulo","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center (K.A.L., M.W.P., A.W.C., W.C.N.)."},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, OH (M.W.P., W.C.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-1450","authenticated-orcid":true,"given":"Laura","family":"Southgate","sequence":"additional","affiliation":[{"name":"Molecular & Clinical Sciences Research Institute, St George\u2019s, University of London, United Kingdom (L.S., R.D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7697-7438","authenticated-orcid":true,"given":"Jennifer M.","family":"Martin","sequence":"additional","affiliation":[{"name":"NIHR BioResource for Translational Research, Cambridge, United Kingdom (D.G., K.M., J.M.M., C.J.P., J.C.S., N.W.M., S. Gr\u00e4f)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen M.","family":"Treacy","sequence":"additional","affiliation":[{"name":"Department of Medicine (E.M.S., D.P., T.T., C.M.T., M.R.T., N.W.M., S. Gr\u00e4f), University of Cambridge."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-1450","authenticated-orcid":true,"given":"Christopher J.","family":"Penkett","sequence":"additional","affiliation":[{"name":"Department of Haematology (D.G., K.M., C.J.P., J.C.S., S. Gr\u00e4f), University of Cambridge."},{"name":"NIHR BioResource for Translational Research, Cambridge, United Kingdom (D.G., K.M., J.M.M., C.J.P., J.C.S., N.W.M., S. 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