Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension.
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Published version
Author(s)
Type
Journal Article
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.
Date Issued
2021-02
Date Acceptance
2020-11-29
Citation
Circulation: Genomic and Precision Medicine, 2021, 14 (1), pp.57-70
ISSN
2574-8300
Publisher
American Heart Association
Start Page
57
End Page
70
Journal / Book Title
Circulation: Genomic and Precision Medicine
Volume
14
Issue
1
Copyright Statement
© 2020 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
License URL
Sponsor
British Heart Foundation
The Academy of Medical Sciences
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33320693
Grant Number
FS/15/59/31839
WMET_P76013
Subjects
computed tomography
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-12-15