Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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.
Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.
Circ Genom Precis Med. 2020; 14(1):e003155
Doi: 10.1161/CIRCGEN.120.003155
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Kovacs Gabor
- Olschewski Horst
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- 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.
- Find related publications in this database (Keywords)
- computed tomography
- family history
- genetic association studies
- pulmonary hypertension
- vascular endothelial growth factor receptor