Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Research output: Contribution to journalArticlepeer-review


  • 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
  • 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

Colleges, School and Institutes


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.


Original languageEnglish
Article number1416
Number of pages16
JournalNature Communications
Issue number1
Publication statusPublished - 12 Apr 2018