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Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Lookup NU author(s): Dr James Lordan



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 Lippincott Williams and Wilkins. All rights reserved.Background: 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. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource-Rare 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. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) 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 KDR 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 KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, 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 KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Publication metadata

Author(s): Swietlik EM, Greene D, Zhu N, Megy K, Cogliano M, Rajaram S, Pandya D, Tilly T, Lutz KA, Welch CCL, Pauciulo MW, Southgate L, Martin JM, Treacy CM, Penkett CJ, Stephens JC, Bogaard HJ, Church C, Coghlan G, Coleman AW, Condliffe R, Eichstaedt CA, Eyries M, Gall H, Ghio S, Girerd B, Grunig E, Holden S, Howard L, Humbert M, Kiely DG, Kovacs G, Lordan J, Machado RD, Mackenzie Ross RV, McCabe C, Moledina S, Montani D, Olschewski H, Pepke-Zaba J, Price L, Rhodes CJ, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Vonk Noordegraaf A, Wharton J, Wild JM, Wort SJ, Lawrie A, Wilkins MR, Trembath RC, Shen Y, Chung WK, Swift AJ, Nichols WC, Morrell NW, Graf S

Publication type: Article

Publication status: Published

Journal: Circulation: Genomic and Precision Medicine

Year: 2021

Volume: 14

Issue: 1

Print publication date: 01/02/2021

Online publication date: 15/12/2020

Acceptance date: 29/11/2020

Date deposited: 06/05/2021

ISSN (electronic): 2574-8300

Publisher: Lippincott Williams and Wilkins


DOI: 10.1161/CIRCGEN.120.003155

PubMed id: 33320693


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Funder referenceFunder name
BHF Cambridge Centre of Cardiovascular Research Excellence
BHF Programme grants to R.C. Trembath (RG/08/006/25302)
British Heart Foundation (BHF; SP/12/12/29836 and SP/18/10/33975)
Dinosaur Trust
Dr Lawrie is supported by a BHF Senior Basic Science Research Fellowship (FS/13/48/30453)
Dr Morrell (RG/13/4/30107)
Dr Morrell is a BHF Professor and NIHR Senior Investigator.
NIH investigator-initiated resources grant (R24 HL105333 to Dr Nichols)
UK NIHR National Institute for Health Research Cambridge Biomedical Research Centre
UK Medical Research Council (MR/K020919/1)
UK National Cohort of Idiopathic and Heritable Pulmonary Arterial Hypertension (PAH) is supported by the National Institute for Health Research (NIHR)