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

Emilia Swietlik 1 Daniel Greene 1 Na Zhu 2 Karyn Megy 1 Marcella Cogliano 3 Smitha Rajaram 3 Divya Pandya 1 Tobias Tilly 1 Katie Lutz 4 Carrie C.L. Welch 2 Michael Pauciulo 4 Laura Southgate 5 Jennifer Martin 1 Carmen Treacy 1 Christopher Penkett 1 Jonathan Stephens 1 Harm Bogaard 6 Colin Church 7 Gerry Coghlan 8 Anna Coleman 4 Robin Condliffe 3 Christina Eichstaedt 9 Mélanie Eyries 10, 11 Henning Gall 12 Stefano Ghio 13 Barbara Girerd 14 Ekkehard Grünig 15 Simon Holden 16 Luke Howard 17 Marc Humbert 14 David Kiely 18 Gabor Kovacs 19 Jim Lordan 20 Rajiv Machado 5 Robert Mackenzie Ross 21 Colm Mccabe 17 Shahin Moledina 22 David Montani 14 Horst Olschewski 19 Joanna Pepke-Zaba 23 Laura Price 17 Christopher Rhodes 17 Werner Seeger 12 Florent Soubrier 10, 11 Jay Suntharalingam 21 Mark Toshner 1 Anton Vonk Noordegraaf 6 John Wharton 17 James Wild 3 Stephen John Wort 17 Allan Lawrie 3 Martin Wilkins 17 Richard Trembath 24 Yufeng Shen 2 Wendy Chung 2 Andrew Swift 3 William Nichols 4 Nicholas Morrell 1 Stefan Gräf 1
Abstract : 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 NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), 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 (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=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 five 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 Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), 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.
Keywords : computed tomography
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Contributor : Gestionnaire Hal-Su <>
Submitted on : Friday, January 8, 2021 - 4:14:46 PM
Last modification on : Friday, February 26, 2021 - 10:58:04 AM


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Emilia Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, et al.. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension. Circulation: Genomic and Precision Medicine, American Heart Association, 2020, ⟨10.1161/CIRCGEN.120.003155⟩. ⟨hal-03104099⟩



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