Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Stefan Gräf (), Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M. Salmon, Mark Southwood, Rajiv D. Machado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Micheala Aldred, Harm J. Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Robert V. MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrea Olschewski, Horst Olschewski, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Dan F. Stein, Jay Suntharalingam, Emilia M. Swietlik, Mark R. Toshner, David A. van Heel, Anton Vonk Noordegraaf, Quinten Waisfisz, John Wharton, Stephen J. Wort, Willem H. Ouwehand, Nicole Soranzo, Allan Lawrie, Paul D. Upton, Martin R. Wilkins, Richard C. Trembath and Nicholas W. Morrell ()
Additional contact information
Stefan Gräf: University of Cambridge
Matthias Haimel: University of Cambridge
Marta Bleda: University of Cambridge
Charaka Hadinnapola: University of Cambridge
Laura Southgate: St George’s, University of London
Wei Li: University of Cambridge
Joshua Hodgson: University of Cambridge
Bin Liu: University of Cambridge
Richard M. Salmon: University of Cambridge
Mark Southwood: Royal Papworth Hospital
Rajiv D. Machado: St George’s University of London
Jennifer M. Martin: University of Cambridge
Carmen M. Treacy: University of Cambridge
Katherine Yates: University of Cambridge
Louise C. Daugherty: University of Cambridge
Olga Shamardina: University of Cambridge
Deborah Whitehorn: University of Cambridge
Simon Holden: Addenbrooke’s Hospital
Micheala Aldred: Cleveland Clinic, Cleveland
Harm J. Bogaard: VU University Medical Center
Colin Church: Golden Jubilee National Hospital
Gerry Coghlan: Royal Free Hospital
Robin Condliffe: Royal Hallamshire Hospital
Paul A. Corris: University of Newcastle
Cesare Danesino: University of Pavia
Mélanie Eyries: Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités
Henning Gall: University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary System (ECCCPS)
Stefano Ghio: Fondazione IRCCS Policlinico San Matteo
Hossein-Ardeschir Ghofrani: University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary System (ECCCPS)
J. Simon R. Gibbs: National Heart & Lung Institute, Imperial College London
Barbara Girerd: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay; AP-HP, Service de Pneumologie, Centre de référence de l’hypertension pulmonaire; INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre
Arjan C. Houweling: VU University Medical Center
Luke Howard: Imperial College London
Marc Humbert: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay; AP-HP, Service de Pneumologie, Centre de référence de l’hypertension pulmonaire; INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre
David G. Kiely: Royal Hallamshire Hospital
Gabor Kovacs: Ludwig Boltzmann Institute for Lung Vascular Research
Robert V. MacKenzie Ross: Royal United Hospitals Bath NHS Foundation Trust
Shahin Moledina: Great Ormond Street Hospital
David Montani: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay; AP-HP, Service de Pneumologie, Centre de référence de l’hypertension pulmonaire; INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre
Michael Newnham: University of Cambridge
Andrea Olschewski: Ludwig Boltzmann Institute for Lung Vascular Research
Horst Olschewski: Ludwig Boltzmann Institute for Lung Vascular Research
Andrew J. Peacock: Golden Jubilee National Hospital
Joanna Pepke-Zaba: Royal Papworth Hospital
Inga Prokopenko: Imperial College London
Christopher J. Rhodes: Imperial College London
Laura Scelsi: Fondazione IRCCS Policlinico San Matteo
Werner Seeger: University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary System (ECCCPS)
Florent Soubrier: Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités
Dan F. Stein: University of Cambridge
Jay Suntharalingam: Royal United Hospitals Bath NHS Foundation Trust
Emilia M. Swietlik: University of Cambridge
Mark R. Toshner: University of Cambridge
David A. van Heel: Queen Mary University of London
Anton Vonk Noordegraaf: VU University Medical Center
Quinten Waisfisz: VU University Medical Center
John Wharton: Imperial College London
Stephen J. Wort: Imperial College London
Willem H. Ouwehand: University of Cambridge
Nicole Soranzo: University of Cambridge
Allan Lawrie: University of Sheffield
Paul D. Upton: University of Cambridge
Martin R. Wilkins: Imperial College London
Richard C. Trembath: King’s College London
Nicholas W. Morrell: University of Cambridge

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03672-4

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