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. BogaardColin 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

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish
Article number1416
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

Fingerprint

hypertension
Type II Bone Morphogenetic Protein Receptors
Pulmonary Hypertension
Genes
mutations
Transforming Growth Factors
Mutation
genes
bones
Ligands
proteins
secretions
sequencing
prognosis
Familial Primary Pulmonary Hypertension
genome
coding
Genome
disorders
ligands

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Gräf, S., Haimel, M., Bleda, M., Hadinnapola, C., Southgate, L., Li, W., ... Stein, D. F. (2018). Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nature Communications, 9(1), [1416]. https://doi.org/10.1038/s41467-018-03672-4

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. / 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.

In: Nature Communications, Vol. 9, No. 1, 1416, 01.12.2018.

Research output: Contribution to journalArticle

Gräf, S, Haimel, M, Bleda, M, Hadinnapola, C, Southgate, L, Li, W, Hodgson, J, Liu, B, Salmon, RM, Southwood, M, Machado, RD, Martin, JM, Treacy, CM, Yates, K, Daugherty, LC, Shamardina, O, Whitehorn, D, Holden, S, Aldred, M, Bogaard, HJ, Church, C, Coghlan, G, Condliffe, R, Corris, PA, Danesino, C, Eyries, M, Gall, H, Ghio, S, Ghofrani, HA, Gibbs, JSR, Girerd, B, Houweling, AC, Howard, L, Humbert, M, Kiely, DG, Kovacs, G, MacKenzie Ross, RV, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, AJ, Pepke-Zaba, J, Prokopenko, I, Rhodes, CJ, Scelsi, L, Seeger, W, Soubrier, F & Stein, DF 2018, 'Identification of rare sequence variation underlying heritable pulmonary arterial hypertension', Nature Communications, vol. 9, no. 1, 1416. https://doi.org/10.1038/s41467-018-03672-4
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. / Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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AU - Li, Wei

AU - Hodgson, Joshua

AU - Liu, Bin

AU - Salmon, Richard M.

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AU - Bogaard, Harm J.

AU - Church, Colin

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AU - Corris, Paul A.

AU - Danesino, Cesare

AU - Eyries, Mélanie

AU - Gall, Henning

AU - Ghio, Stefano

AU - Ghofrani, Hossein Ardeschir

AU - Gibbs, J. Simon R.

AU - Girerd, Barbara

AU - Houweling, Arjan C.

AU - Howard, Luke

AU - Humbert, Marc

AU - Kiely, David G.

AU - Kovacs, Gabor

AU - MacKenzie Ross, Robert V.

AU - Moledina, Shahin

AU - Montani, David

AU - Newnham, Michael

AU - Olschewski, Andrea

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AU - Peacock, Andrew J.

AU - Pepke-Zaba, Joanna

AU - Prokopenko, Inga

AU - Rhodes, Christopher J.

AU - Scelsi, Laura

AU - Seeger, Werner

AU - Soubrier, Florent

AU - Stein, Dan F.

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