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.

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Item Type:	Article
Authors/Creators:	Graf, 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. Bogaard, H.J. Church, C. Coghlan, G. Condliffe, R. Corris, P.A. Danesino, C. Eyries, M. Gall, H. Ghio, S. Ghofrani, H.-A. Gibbs, J.S.R. Girerd, B. Houweling, A.C. Howard, L. Humbert, M. Kiely, D.G. https://orcid.org/0000-0003-0184-6502 Kovacs, G. Ross, R.V.M. Moledina, S. Montani, D. Newnham, M. Olschewski, A. Olschewski, H. Peacock, A.J. Pepke-Zaba, J. Prokopenko, I. Rhodes, C.J. Scelsi, L. Seeger, W. Soubrier, F. Stein, D.F. Suntharalingam, J. Swietlik, E.M. Toshner, M.R. van Heel, D.A. Noordegraaf, A.V. Waisfisz, Q. Wharton, J. Wort, S.J. Ouwehand, W.H. Soranzo, N. Lawrie, A. https://orcid.org/0000-0003-4192-9505 Upton, P.D. Wilkins, M.R. Trembath, R.C. Morrell, N.W.
Copyright, Publisher and Additional Information:	© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 2 March 2018 Published: 12 April 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	24 May 2018 10:50
Last Modified:	10 Nov 2018 02:33
Published Version:	https://doi.org/10.1038/s41467-018-03672-4
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	10.1038/s41467-018-03672-4
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:131096

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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

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