TY - JOUR
T1 - Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension
AU - morrell
AU - Swietlik, Emilia M
AU - Greene, Daniel
AU - Zhu, Na
AU - Megy, Karyn
AU - Cogliano, Marcella
AU - Rajaram, Smitha
AU - Pandya, Divya
AU - Tilly, Tobias
AU - Lutz, Katie A
AU - Welch, Carrie C L
AU - Pauciulo, Michael W
AU - Southgate, Laura
AU - Martin, Jennifer M
AU - Treacy, Carmen M
AU - Penkett, Christopher J
AU - Stephens, Jonathan C
AU - Bogaard, Harm J
AU - Church, Colin
AU - Coghlan, Gerry
AU - Coleman, Anna W
AU - Condliffe, Robin
AU - Eichstaedt, Christina A
AU - Eyries, Mélanie
AU - Gall, Henning
AU - Ghio, Stefano
AU - Girerd, Barbara
AU - Grünig, Ekkehard
AU - Holden, Simon
AU - Howard, Luke
AU - Humbert, Marc
AU - Kiely, David G
AU - Kovacs, Gabor
AU - Lordan, Jim
AU - Machado, Rajiv D
AU - Mackenzie Ross, Robert V
AU - McCabe, Colm
AU - Moledina, Shahin
AU - Montani, David
AU - Olschewski, Horst
AU - Pepke-Zaba, Joanna
AU - Price, Laura
AU - Rhodes, Christopher J
AU - Seeger, Werner
AU - Soubrier, Florent
AU - Suntharalingam, Jay
AU - Toshner, Mark R
AU - Vonk Noordegraaf, Anton
AU - Wharton, John
AU - Wild, James M
AU - Wort, Stephen John
N1 - Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - computed tomography
KW - family history
KW - genetic association studies
KW - pulmonary hypertension
KW - vascular endothelial growth factor receptor
UR - http://www.scopus.com/inward/record.url?scp=85104495698&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/CIRCGEN.120.003155
DO - https://doi.org/10.1161/CIRCGEN.120.003155
M3 - Article
C2 - 33320693
SN - 2574-8300
VL - 14
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 1
M1 - e003155
ER -