Identification of novel rare sequence variation underlying heritable pulmonary arterial hypertension
Author:
Gräf StefanORCID, Haimel Matthias, Bleda Marta, Hadinnapola Charaka, Southgate Laura, Li Wei, Hodgson Joshua, Liu Bin, Salmon Richard M., Southwood Mark, Machado Rajiv D., Martin Jennifer M., Treacy Carmen M., Yates Katherine, Daugherty Louise C., Shamardina Olga, Whitehorn Deborah, Holden Simon, Aldred Micheala, Bogaard Harm J., Church Colin, Coghlan Gerry, Condliffe Robin, Corris Paul A., Danesino Cesare, Eyries Mélanie, Gall Henning, Ghio Stefano, Ghofrani Hossein-Ardeschir, Gibbs J. Simon R., Girerd Barbara, Houweling Arjan C., Howard Luke, Humbert Marc, Kiely David G., Kovacs Gabor, MacKenzie Ross Robert V., Moledina Shahin, Montani David, Newnham Michael, Olschewski Andrea, Olschewski Horst, Peacock Andrew J., Pepke-Zaba Joanna, Prokopenko Inga, Rhodes Christopher J., Scelsi Laura, Seeger Werner, Soubrier Florent, Stein Dan F., Suntharalingam Jay, Swietlik Emilia, Toshner Mark R., Vonk Noordegraaf Anton, van Heel David A., Waisfisz Quinten, Wharton John, Wort Stephen J., Ouwehand Willem H., Soranzo Nicole, Lawrie Allan, Upton Paul D., Wilkins Martin R.ORCID, Trembath Richard C.ORCID, Morrell Nicholas W.ORCID
Abstract
AbstractPulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
Publisher
Cold Spring Harbor Laboratory
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