GermlineBMP9mutation causes idiopathic pulmonary arterial hypertension

Background Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease with high heritability. Although several predisposing genes have been linked to IPAH, the genetic aetiology remains unknown for a large number of IPAH cases. Methods We conducted an exome-wide gene-based burden analysis on two independent case–control studies, including a total of 331 IPAH cases and 10 508 controls. Functional assessments were conducted to analyse the effects of genetic mutations on protein biosynthesis and function. Results The gene encoding human bone morphogenetic protein 9 ( BMP9 ) was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (OR 18.8; p=1.9×10 −11 ). This association was authenticated in the independent replication cohort (p=1.0×10 −5 ). Collectively, the rare coding mutations in BMP9 occurred in 6.7% of cases, ranking this gene second to BMPR2 , comprising a combined significance of 2.7×10 −19 (OR 21.2). Intriguingly, the patients with BMP9 mutations had lower plasma levels of BMP9 than those without. Functional studies showed that the BMP9 mutations led to reduced BMP9 secretion and impaired anti-apoptosis ability in pulmonary arterial endothelial cells. Conclusion We identify BMP9 as an IPAH culprit gene.