Germline mutation 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 () was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (OR 18.8; p=1.9×10). This association was authenticated in the independent replication cohort (p=1.0×10). Collectively, the rare coding mutations in occurred in 6.7% of cases, ranking this gene second to , comprising a combined significance of 2.7×10 (OR 21.2). Intriguingly, the patients with mutations had lower plasma levels of BMP9 than those without. Functional studies showed that the mutations led to reduced BMP9 secretion and impaired anti-apoptosis ability in pulmonary arterial endothelial cells.

Conclusion: We identify as an IPAH culprit gene.