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.

中文翻译：

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贝叶斯推理将罕见的 KDR 变异与肺动脉高压的特定表型联系起来


背景：大约 25% 的肺动脉高压 (PAH) 患者被发现携带罕见的致病基因突变。为了确定 PAH 中缺失的遗传性，我们使用贝叶斯统计将深度表型分析与全基因组测序数据相结合。方法：我们分析了参加 NBR 研究（NIHR BioResource—罕见疾病）的 13 037 名参与者，其中 1148 名参与者被招募到 PAH 领域。为了测试基因与选定的肺动脉高压表型之间的遗传关联，我们使用了贝叶斯罕见变异关联方法 BeviMed。结果：激酶插入结构域受体 ( KDR ) 基因中的杂合、高影响、可能功能丧失的变异强烈存在。与一氧化碳转移系数显着降低（后验概率=0.989）和诊断时年龄较大（后验概率=0.912）相关。我们还提供了具有这些表型的罕见无义KDR变体的家族分离的证据。在肺部计算机断层扫描成像中，在携带这些预测的KDR有害变异的 5 名患者中观察到一系列实质异常。在美国 PAH 生物库队列中独立鉴定出另外 4 例具有KDR罕见可能功能丧失变异的 PAH 病例，具有相似的表型特征。结论：贝叶斯推理方法使我们能够独立验证KDR ，它编码 VEGFR2（血管内皮细胞）。生长因子受体2)，作为一种新的PAH候选基因。此外，这种方法特别将遗传受限基因中具有高影响力的可能功能丧失的变异与不同的表型相关联。 这些发现为KDR是一种临床上可操作的 PAH 基因提供了证据，并进一步支持血管内皮在 PAH 病理学中的核心作用。