Title |
Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
|
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Published in |
Nature Communications, April 2018
|
DOI | 10.1038/s41467-018-03672-4 |
Pubmed ID | |
Authors |
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, Nicholas W. Morrell |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 9 | 23% |
United States | 5 | 13% |
Italy | 2 | 5% |
Switzerland | 2 | 5% |
Saudi Arabia | 2 | 5% |
Spain | 1 | 3% |
Germany | 1 | 3% |
Venezuela, Bolivarian Republic of | 1 | 3% |
United Arab Emirates | 1 | 3% |
Other | 6 | 15% |
Unknown | 9 | 23% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 25 | 64% |
Scientists | 10 | 26% |
Science communicators (journalists, bloggers, editors) | 2 | 5% |
Practitioners (doctors, other healthcare professionals) | 2 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 224 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 34 | 15% |
Researcher | 31 | 14% |
Student > Bachelor | 24 | 11% |
Student > Master | 19 | 8% |
Other | 11 | 5% |
Other | 38 | 17% |
Unknown | 67 | 30% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 54 | 24% |
Medicine and Dentistry | 43 | 19% |
Agricultural and Biological Sciences | 26 | 12% |
Pharmacology, Toxicology and Pharmaceutical Science | 8 | 4% |
Computer Science | 4 | 2% |
Other | 17 | 8% |
Unknown | 72 | 32% |