%0 Journal Article %A Emilia Świetlik %A Katie A Lutz %A Daniel Greene %A Michael W Pauciulo %A Tobias Tilly %A Divya Pandya %A Na Zhu %A Marcella Cogliano %A Carrie L Welch %A Anna W Coleman %A N.I.H.R Bioresource Rare Diseases Consortium %A Yufeng Shen %A Andrew Swift %A Wendy Chung %A William C Nichols %A Nick W Morrell %A Stefan Graf %T New rare variant associations with distinct phenotypes in patients with pulmonary arterial hypertension revealed with Bayesian inference %D 2020 %R 10.1183/13993003.congress-2020.4459 %J European Respiratory Journal %P 4459 %V 56 %N suppl 64 %X Background: Up to 25% of idiopathic and > 70% of cases with familial pulmonary arterial hypertension (PAH) can be explained by rare deleterious variants in established PAH risk genes.We hypothesised that integrating deep phenotyping with whole-genome sequencing (WGS) data will reveal additional disease variants that are ultra-rare and/or have a unique phenotypic signature.Methods: We analysed WGS data from 1,148 PAH patients and 11,889 controls enrolled in the NIHR BioResource-Rare Diseases study. We used a Bayesian model comparison method (BeviMed) to test for genotype-phenotype associations. Case-control labels were defined by diagnostic groupings and KCO and age strata. Competing models were fitted to identify associations between labels and rare variants under the dominant and recessive mode of inheritance and different variant consequence types.Results: We discovered a strong association between the protein-truncating variants (PTV) in KDR, which encodes VEGFR2, and PAH with low KCO (posterior probability (PP)=0.99) and older age at diagnosis (PP=0.91). Lung CT scans of patients harbouring PTV in KDR revealed a range of mild parenchymal abnormalities. One KDR subject had a family history of PAH. KCO stratification also highlighted an association between IDH3G and moderately reduced KCO in patients with PAH (PP=0.92). The US PAH Biobank was used to validate these findings and identified 4 additional PAH cases with PTVs in KDR and 3 in IDH3G.Conclusions: The smart study design allowed the discovery of new PAH risk, which further implicate central roles for the endothelium and alterations in mitochondrial respiration in PAHFootnotesCite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 4459.This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only). %U