PT - JOURNAL ARTICLE AU - Emilia M. Swietlik AU - Daniel Greene AU - Na Zhu AU - Karyn Megy AU - Marcella Cogliano AU - Smitha Rajaram AU - Divya Pandya AU - Tobias Tilly AU - Katie A. Lutz AU - Carrie C. L. Welch AU - Michael W. Pauciulo AU - Laura Southgate AU - Jennifer M. Martin AU - Carmen M. Treacy AU - Harm J. Bogaard AU - Colin Church AU - Gerry Coghlan AU - Anna W. Coleman AU - Robin Condliffe AU - Mélanie Eyries AU - Henning Gall AU - Stefano Ghio AU - Barbara Girerd AU - Simon Holden AU - Luke Howard AU - Marc Humbert AU - David G. Kiely AU - Gabor Kovacs AU - Jim Lordan AU - Rajiv D. Machado AU - Robert V. MacKenzie Ross AU - Shahin Moledina AU - David Montani AU - Horst Olschewski AU - Joanna Pepke-Zaba AU - Christopher J. Rhodes AU - Werner Seeger AU - Florent Soubrier AU - Jay Suntharalingam AU - Mark R. Toshner AU - Anton Vonk Noordegraaf AU - John Wharton AU - Jim Wild AU - Stephen John Wort AU - NIHR BioResource for Translational Research - Rare Diseases AU - National Cohort Study of Idiopathic and Heritable PAH AU - PAH Biobank Enrolling Centers’ Investigators AU - Allan Lawrie AU - Martin R. Wilkins AU - Richard C. Trembath AU - Yufeng Shen AU - Wendy K. Chung AU - Andrew J. Swift AU - William C. Nichols AU - Nicholas W. Morrell AU - Stefan Gräf TI - Reduced transfer coefficient of carbon monoxide in pulmonary arterial hypertension implicates rare protein-truncating variants in <em>KDR</em> AID - 10.1101/2019.12.11.871210 DP - 2019 Jan 01 TA - bioRxiv PG - 2019.12.11.871210 4099 - http://biorxiv.org/content/early/2019/12/22/2019.12.11.871210.short 4100 - http://biorxiv.org/content/early/2019/12/22/2019.12.11.871210.full AB - Background To date, approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbour rare mutations in disease-causing genes. Given the small number of patients affected by mutations in most PAH genes, the identification of the missing heritability in PAH is challenging. We hypothesised that integrating deep phenotyping data with whole-genome sequencing data will reveal additional disease variants that are extremely rare and/or have a unique phenotypic signature.Methods We analysed whole-genome sequencing data from 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NIHRBR-RD) study, of which 1148 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. We defined the groups for comparison by assigning labels (‘tags’) inferred from the current diagnostic classification of PAH, stratification by age at diagnosis and transfer coefficient of carbon monoxide (KCO).Results Protein truncating variants (PTV) in KDR were strongly associated with the lower KCO tertile (posterior probability (PP)=0.989) and the higher age tertile (PP=0.912) groups. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the patients harbouring PTV in KDR. KCO stratification also highlighted an association between Isocitrate Dehydrogenase (NAD(+)) 3 Non-Catalytic Subunit Gamma (IDH3G) and moderately reduced KCO in patients with pulmonary hypertension (PP=0.920). The US PAH Biobank was used to independently validate these findings and identified four additional PAH cases with PTV in KDR and two in IDH3G. We confirmed associations between previously established genes and PAH.Conclusions PTVs in KDR, the gene encoding vascular endothelial growth factor receptor 2 (VEGFR2), are significantly associated with two specific phenotypes of PAH, reduced KCO and later age of onset, highlighting a role for VEGF signalling in the pathogenesis of human PAH. We also report IDH3G as a new PAH risk gene. Moreover, we demonstrate that the use of deep clinical phenotyping data advances the identification of novel causative rare variants.