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Although several predisposing genes have been linked to IPAH, the genetic aetiology remains unknown for a large number of IPAH cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted an exome-wide gene-based burden analysis on two independent case\u2013control studies, including a total of 331 IPAH cases and 10\u200a508 controls. Functional assessments were conducted to analyse the effects of genetic mutations on protein biosynthesis and function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The gene encoding human bone morphogenetic protein 9 (<jats:italic>BMP9<\/jats:italic>) was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (OR 18.8; p=1.9\u00d710<jats:sup>\u221211<\/jats:sup>). This association was authenticated in the independent replication cohort (p=1.0\u00d710<jats:sup>\u22125<\/jats:sup>). Collectively, the rare coding mutations in<jats:italic>BMP9<\/jats:italic>occurred in 6.7% of cases, ranking this gene second to<jats:italic>BMPR2<\/jats:italic>, comprising a combined significance of 2.7\u00d710<jats:sup>\u221219<\/jats:sup>(OR 21.2). Intriguingly, the patients with<jats:italic>BMP9<\/jats:italic>mutations had lower plasma levels of BMP9 than those without. Functional studies showed that the<jats:italic>BMP9<\/jats:italic>mutations led to reduced BMP9 secretion and impaired anti-apoptosis ability in pulmonary arterial endothelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identify<jats:italic>BMP9<\/jats:italic>as an IPAH culprit gene.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.01609-2018","type":"journal-article","created":{"date-parts":[[2018,12,21]],"date-time":"2018-12-21T19:42:15Z","timestamp":1545421335000},"page":"1801609","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":137,"title":["Germline<i>BMP9<\/i>mutation causes idiopathic pulmonary arterial 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