Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Stefan Graf; 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; Melanie 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; Nicholas W. Morrell

doi:10.1038/s41467-018-03672-4

Back

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Journal article

Open access

Peer reviewed

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Stefan Graf, Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M. Salmon, Mark Southwood, …

Nature communications, Vol.9(1), pp.1416-16

12/04/2018

DOI: https://doi.org/10.1038/s41467-018-03672-4

PMID: 29650961

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-beta 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.

Files and links (1)

url

https://doi.org/10.1038/s41467-018-03672-4View

Published (Version of record) Open

Metrics

1 Record Views

255 Times Cited - Web of Science

See more details

Details

Title: Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
Creators: Stefan Graf - 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 - 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
Harm J. Bogaard - Amsterdam UMC Location VUmc
Colin Church - Golden Jubilee National Hospital
Gerry Coghlan - The Royal Free Hospital
Robin Condliffe - Royal Hallamshire Hospital
Paul A. Corris - Newcastle University
Cesare Danesino - University of Pavia
Melanie Eyries - Inserm
Henning Gall - Universities of Giessen and Marburg Lung Center
Stefano Ghio - Policlinico San Matteo Fondazione
Hossein-Ardeschir Ghofrani - Universities of Giessen and Marburg Lung Center
J. Simon R. Gibbs - Imperial College London
Barbara Girerd - Bicêtre Hospital
Arjan C. Houweling - Amsterdam UMC Location VUmc
Luke Howard - Imperial College London
Marc Humbert - Université Paris-Saclay
David G. Kiely - Royal Hallamshire Hospital
Gabor Kovacs - Ludwig Boltzmann Institute for Lung Vascular Research
Robert V. MacKenzie Ross - Royal United Hospital Bath NHS Trust
Shahin Moledina - Great Ormond Street Hospital
David Montani - Université Paris-Saclay
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 Hosp, Cambridge CB23 3RE, England
Inga Prokopenko - Imperial College London
Christopher J. Rhodes - Imperial College London
Laura Scelsi - Policlinico San Matteo Fondazione
Werner Seeger - Universities of Giessen and Marburg Lung Center
Florent Soubrier - Inserm
Dan F. Stein - University of Cambridge
Jay Suntharalingam - Royal United Hospital Bath NHS 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 - Amsterdam UMC Location VUmc
Quinten Waisfisz - Amsterdam UMC Location VUmc
John Wharton - Imperial College London
Stephen J. Wort - Imperial College London
Willem H. Ouwehand - University of Cambridge
Nicole Soranzo - Wellcome Sanger Institute
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
Publication Details: Nature communications, Vol.9(1), pp.1416-16
Publisher: NATURE PORTFOLIO
Number of pages: 16
Date published: 12/04/2018
Grant note: BHF Cambridge Centre of Cardiovascular Research Excellence Imperial NIHR Clinical Research Facility Dutch Federation of University Medical Centres MR/K020919/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Dutch Heart Foundation; Netherlands Heart Foundation RG/08/006/25302; RG/13/4/30107 / Dinosaur Trust, BHF Programme grants FS/13/48/30453 / BHF Senior Basic Science Research Fellowship MR/K020919/1 / UK Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) MGU0205 / Bart's Charity award FS/15/59/31839 / BHF Intermediate Basic Science Research Fellowship
Identifiers: 99928705202346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Abstract

Files and links (1)

Metrics

Details

Usage Policy