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; Richard C. Trembath

doi:10.1038/s41467-018-03672-4

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, Richard C. Trembath

^*Corresponding author for this work

Medical & Molecular Genetics

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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.

Original language	English
Article number	1416
Journal	Nature Communications
Volume	9
Early online date	12 Apr 2018
DOIs	https://doi.org/10.1038/s41467-018-03672-4
Publication status	Published - 30 Apr 2018

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Identification of rare sequence_GRAF_Accepted2March2018_GOLD VoR Final published version, 7.28 MBLicence: CC BY

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Gräf, S., Haimel, M., Bleda, M., Hadinnapola, C., Southgate, L., Li, W., Hodgson, J., Liu, B., Salmon, R. M., Southwood, M., Machado, R. D., Martin, J. M., Treacy, C. M., Yates, K., Daugherty, L. C., Shamardina, O., Whitehorn, D., Holden, S., Aldred, M., ... Trembath, R. C. (2018). Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nature Communications, 9, Article 1416. https://doi.org/10.1038/s41467-018-03672-4

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title = "Identification of rare sequence variation underlying heritable pulmonary arterial hypertension",

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.",

author = "Stefan Gr{\"a}f and Matthias Haimel and Marta Bleda and Charaka Hadinnapola and Laura Southgate and Wei Li and Joshua Hodgson and Bin Liu and Salmon, {Richard M.} and Mark Southwood and Machado, {Rajiv D.} and Martin, {Jennifer M.} and Treacy, {Carmen M.} and Katherine Yates and Daugherty, {Louise C.} and Olga Shamardina and Deborah Whitehorn and Simon Holden and Micheala Aldred and Bogaard, {Harm J.} and Colin Church and Gerry Coghlan and Robin Condliffe and Corris, {Paul A.} and Cesare Danesino and M{\'e}lanie Eyries and Henning Gall and Stefano Ghio and Ghofrani, {Hossein Ardeschir} and Gibbs, {J. Simon R.} and Barbara Girerd and Houweling, {Arjan C.} and Luke Howard and Marc Humbert and Kiely, {David G.} and Gabor Kovacs and {MacKenzie Ross}, {Robert V.} and Shahin Moledina and David Montani and Michael Newnham and Andrea Olschewski and Horst Olschewski and Peacock, {Andrew J.} and Joanna Pepke-Zaba and Inga Prokopenko and Rhodes, {Christopher J.} and Laura Scelsi and Werner Seeger and Florent Soubrier and Trembath, {Richard C.}",

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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 & Trembath, RC 2018, 'Identification of rare sequence variation underlying heritable pulmonary arterial hypertension', Nature Communications, vol. 9, 1416. https://doi.org/10.1038/s41467-018-03672-4

TY - JOUR

T1 - Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

AU - Gräf, Stefan

AU - Haimel, Matthias

AU - Bleda, Marta

AU - Hadinnapola, Charaka

AU - Southgate, Laura

AU - Li, Wei

AU - Hodgson, Joshua

AU - Liu, Bin

AU - Salmon, Richard M.

AU - Southwood, Mark

AU - Machado, Rajiv D.

AU - Martin, Jennifer M.

AU - Treacy, Carmen M.

AU - Yates, Katherine

AU - Daugherty, Louise C.

AU - Shamardina, Olga

AU - Whitehorn, Deborah

AU - Holden, Simon

AU - Aldred, Micheala

AU - Bogaard, Harm J.

AU - Church, Colin

AU - Coghlan, Gerry

AU - Condliffe, Robin

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

AU - Olschewski, Horst

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 - Trembath, Richard C.

PY - 2018/4/30

Y1 - 2018/4/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85045505608&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-03672-4

DO - 10.1038/s41467-018-03672-4

M3 - Article

AN - SCOPUS:85045505608

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 1416

ER -

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Abstract

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