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

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

doi:10.1161/CIRCGEN.120.003155

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

Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. ColemanRobin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. Mackenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

33 Citations (Scopus)

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 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.

Original language	English
Journal	Circulation: Genomic and Precision Medicine
DOIs	https://doi.org/10.1161/CIRCGEN.120.003155
Publication status	Accepted/In press - 2021

Keywords

computed tomography
family history
genetic association studies
pulmonary hypertension
vascular endothelial growth factor receptor

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10.1161/CIRCGEN.120.003155

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Swietlik, E. M., Greene, D., Zhu, N., Megy, K., Cogliano, M., Rajaram, S., Pandya, D., Tilly, T., Lutz, K. A., Welch, C. C. L., Pauciulo, M. W., Southgate, L., Martin, J. M., Treacy, C. M., Penkett, C. J., Stephens, J. C., Bogaard, H. J., Church, C., Coghlan, G., ... Gräf, S. (Accepted/In press). Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension. Circulation: Genomic and Precision Medicine. https://doi.org/10.1161/CIRCGEN.120.003155

@article{f5f988ac7c5f4c7eb01ecf4aee882668,

title = "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 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.",

keywords = "computed tomography, family history, genetic association studies, pulmonary hypertension, vascular endothelial growth factor receptor",

author = "Swietlik, {Emilia M.} and Daniel Greene and Na Zhu and Karyn Megy and Marcella Cogliano and Smitha Rajaram and Divya Pandya and Tobias Tilly and Lutz, {Katie A.} and Welch, {Carrie C.L.} and Pauciulo, {Michael W.} and Laura Southgate and Martin, {Jennifer M.} and Treacy, {Carmen M.} and Penkett, {Christopher J.} and Stephens, {Jonathan C.} and Bogaard, {Harm J.} and Colin Church and Gerry Coghlan and Coleman, {Anna W.} and Robin Condliffe and Eichstaedt, {Christina A.} and M{\'e}lanie Eyries and Henning Gall and Stefano Ghio and Barbara Girerd and Ekkehard Gr{\"u}nig and Simon Holden and Luke Howard and Marc Humbert and Kiely, {David G.} and Gabor Kovacs and Jim Lordan and Machado, {Rajiv D.} and {Mackenzie Ross}, {Robert V.} and Colm McCabe and Shahin Moledina and David Montani and Horst Olschewski and Joanna Pepke-Zaba and Laura Price and Rhodes, {Christopher J.} and Werner Seeger and Florent Soubrier and Jay Suntharalingam and Toshner, {Mark R.} and {Vonk Noordegraaf}, Anton and John Wharton and Wild, {James M.} and Wort, {Stephen John} and Allan Lawrie and Wilkins, {Martin R.} and Trembath, {Richard C.} and Yufeng Shen and Chung, {Wendy K.} and Swift, {Andrew J.} and Nichols, {William C.} and Morrell, {Nicholas W.} and Stefan Gr{\"a}f",

year = "2021",

doi = "10.1161/CIRCGEN.120.003155",

language = "English",

journal = "Circulation: Genomic and Precision Medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins Ltd.",

}

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, Grünig, 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 & Gräf, S 2021, 'Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension', Circulation: Genomic and Precision Medicine. https://doi.org/10.1161/CIRCGEN.120.003155

TY - JOUR

T1 - Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

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

AU - Lawrie, Allan

AU - Wilkins, Martin R.

AU - Trembath, Richard C.

AU - Shen, Yufeng

AU - Chung, Wendy K.

AU - Swift, Andrew J.

AU - Nichols, William C.

AU - Morrell, Nicholas W.

AU - Gräf, Stefan

PY - 2021

Y1 - 2021

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 - 10.1161/CIRCGEN.120.003155

DO - 10.1161/CIRCGEN.120.003155

M3 - Article

C2 - 33320693

AN - SCOPUS:85104495698

SN - 2574-8300

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

ER -

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

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