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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Author

Listed:
  • Stefan Gräf

    (University of Cambridge
    University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Matthias Haimel

    (University of Cambridge
    University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Marta Bleda

    (University of Cambridge)

  • Charaka Hadinnapola

    (University of Cambridge)

  • Laura Southgate

    (St George’s, University of London
    King’s College London)

  • Wei Li

    (University of Cambridge)

  • Joshua Hodgson

    (University of Cambridge)

  • Bin Liu

    (University of Cambridge)

  • Richard M. Salmon

    (University of Cambridge)

  • Mark Southwood

    (Royal Papworth Hospital)

  • Rajiv D. Machado

    (St George’s University of London)

  • Jennifer M. Martin

    (University of Cambridge
    University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Carmen M. Treacy

    (University of Cambridge
    Royal Papworth Hospital)

  • Katherine Yates

    (University of Cambridge
    University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Louise C. Daugherty

    (University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Olga Shamardina

    (University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Deborah Whitehorn

    (University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Simon Holden

    (Addenbrooke’s Hospital)

  • Micheala Aldred

    (Cleveland Clinic, Cleveland)

  • Harm J. Bogaard

    (VU University Medical Center)

  • Colin Church

    (Golden Jubilee National Hospital)

  • Gerry Coghlan

    (Royal Free Hospital)

  • Robin Condliffe

    (Royal Hallamshire Hospital)

  • Paul A. Corris

    (University of Newcastle)

  • Cesare Danesino

    (University of Pavia
    Fondazione IRCCS Policlinico San Matteo)

  • Mélanie Eyries

    (Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités)

  • Henning Gall

    (University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary System (ECCCPS))

  • Stefano Ghio

    (Fondazione IRCCS Policlinico San Matteo)

  • Hossein-Ardeschir Ghofrani

    (University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary System (ECCCPS)
    Imperial College London)

  • J. Simon R. Gibbs

    (National Heart & Lung Institute, Imperial College London)

  • Barbara Girerd

    (Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay; AP-HP, Service de Pneumologie, Centre de référence de l’hypertension pulmonaire; INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre)

  • Arjan C. Houweling

    (VU University Medical Center)

  • Luke Howard

    (Imperial College London)

  • Marc Humbert

    (Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay; AP-HP, Service de Pneumologie, Centre de référence de l’hypertension pulmonaire; INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre)

  • David G. Kiely

    (Royal Hallamshire Hospital)

  • Gabor Kovacs

    (Ludwig Boltzmann Institute for Lung Vascular Research
    Medical University of Graz)

  • Robert V. MacKenzie Ross

    (Royal United Hospitals Bath NHS Foundation Trust)

  • Shahin Moledina

    (Great Ormond Street Hospital)

  • David Montani

    (Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay; AP-HP, Service de Pneumologie, Centre de référence de l’hypertension pulmonaire; INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre)

  • Michael Newnham

    (University of Cambridge)

  • Andrea Olschewski

    (Ludwig Boltzmann Institute for Lung Vascular Research)

  • Horst Olschewski

    (Ludwig Boltzmann Institute for Lung Vascular Research
    Medical University of Graz)

  • Andrew J. Peacock

    (Golden Jubilee National Hospital)

  • Joanna Pepke-Zaba

    (Royal Papworth Hospital)

  • Inga Prokopenko

    (Imperial College London)

  • Christopher J. Rhodes

    (Imperial College London)

  • Laura Scelsi

    (Fondazione IRCCS Policlinico San Matteo)

  • Werner Seeger

    (University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary System (ECCCPS))

  • Florent Soubrier

    (Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités)

  • Dan F. Stein

    (University of Cambridge)

  • Jay Suntharalingam

    (Royal United Hospitals Bath NHS Foundation Trust)

  • Emilia M. Swietlik

    (University of Cambridge)

  • Mark R. Toshner

    (University of Cambridge)

  • David A. van Heel

    (Queen Mary University of London)

  • Anton Vonk Noordegraaf

    (VU University Medical Center)

  • Quinten Waisfisz

    (VU University Medical Center)

  • John Wharton

    (Imperial College London)

  • Stephen J. Wort

    (Imperial College London
    Royal Brompton Hospital)

  • Willem H. Ouwehand

    (University of Cambridge
    NIHR BioResource—Rare Diseases)

  • Nicole Soranzo

    (University of Cambridge
    Wellcome Trust Sanger Institute)

  • Allan Lawrie

    (University of Sheffield)

  • Paul D. Upton

    (University of Cambridge)

  • Martin R. Wilkins

    (Imperial College London)

  • Richard C. Trembath

    (King’s College London)

  • Nicholas W. Morrell

    (University of Cambridge
    NIHR BioResource—Rare Diseases)

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.

Suggested Citation

  • 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 & C, 2018. "Identification of rare sequence variation underlying heritable pulmonary arterial hypertension," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03672-4
    DOI: 10.1038/s41467-018-03672-4
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    Cited by:

    1. Jingxu Guo & Bin Liu & Midory Thorikay & Minmin Yu & Xiaoyan Li & Zhen Tong & Richard M. Salmon & Randy J. Read & Peter ten Dijke & Nicholas W. Morrell & Wei Li, 2022. "Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Hidenori Moriyama & Jin Endo & Masaharu Kataoka & Yuta Shimanaka & Nozomu Kono & Yuki Sugiura & Shinichi Goto & Hiroki Kitakata & Takahiro Hiraide & Naohiro Yoshida & Sarasa Isobe & Tsunehisa Yamamoto, 2022. "Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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