Nature communications · 2018

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

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Gräf Stefan, 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 M, Toshner Mark R, van Heel David A, Vonk Noordegraaf Anton, Waisfisz Quinten, Wharton John, Wort Stephen J, Ouwehand Willem H, Soranzo Nicole, Lawrie Allan, Upton Paul D, Wilkins Martin R, Trembath Richard C, Morrell Nicholas W

Аннотация

Pulmonary 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), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

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