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


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.

SUBMITTER: Swietlik EM 

PROVIDER: S-EPMC7892262 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Bayesian Inference Associates Rare <i>KDR</i> Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.

Swietlik Emilia M EM   Greene Daniel D   Zhu Na N   Megy Karyn K   Cogliano Marcella M   Rajaram Smitha S   Pandya Divya D   Tilly Tobias T   Lutz Katie A KA   Welch Carrie C L CCL   Pauciulo Michael W MW   Southgate Laura L   Martin Jennifer M JM   Treacy Carmen M CM   Penkett Christopher J CJ   Stephens Jonathan C JC   Bogaard Harm J HJ   Church Colin C   Coghlan Gerry G   Coleman Anna W AW   Condliffe Robin R   Eichstaedt Christina A CA   Eyries Mélanie M   Gall Henning H   Ghio Stefano S   Girerd Barbara B   Grünig Ekkehard E   Holden Simon S   Howard Luke L   Humbert Marc M   Kiely David G DG   Kovacs Gabor G   Lordan Jim J   Machado Rajiv D RD   Mackenzie Ross Robert V RV   McCabe Colm C   Moledina Shahin S   Montani David D   Olschewski Horst H   Pepke-Zaba Joanna J   Price Laura L   Rhodes Christopher J CJ   Seeger Werner W   Soubrier Florent F   Suntharalingam Jay J   Toshner Mark R MR   Vonk Noordegraaf Anton A   Wharton John J   Wild James M JM   Wort Stephen John SJ   Lawrie Allan A   Wilkins Martin R MR   Trembath Richard C RC   Shen Yufeng Y   Chung Wendy K WK   Swift Andrew J AJ   Nichols William C WC   Morrell Nicholas W NW   Gräf Stefan S  

Circulation. Genomic and precision medicine 20201215


<b>Background</b> - 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. <b>Methods</b> - 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 a  ...[more]

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