ArticleNature communications2018
Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.
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Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 230 papers, 3 of them syntheses that pooled it.
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230citing papers in PubMed, 3 pooled it
34.5field-weighted citation impact, top 1% of its field
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Who cites it
230 citing papers in PubMed, 3 syntheses or guidelines pooled it, 369 citations in OpenAlex.
- Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve.Circulation · 2026Pooled it
- Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation.Nature communications · 2024Pooled it
- Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.The Lancet. Respiratory medicine · 2019Pooled it
- Genetic variants in pulmonary hypertension associated with chronic obstructive pulmonary disease.Current opinion in pulmonary medicine · 2026Review
- An Ancient Founder GDF2 Variant Potentially Causes Semi-Dominant Non-Syndromic Pulmonary Arterial Hypertension.Clinical genetics · 2026Article
- Artificial Intelligence and Multi-Omics Approaches in the Precision Management of Pulmonary Hypertension: From Early Diagnosis to Therapeutic Stratification.International journal of molecular sciences · 2026Review
- Autophagy-Targeted Vascular Remodeling in Pulmonary Arterial Hypertension: Molecular Mechanisms and Therapeutic Perspectives.Journal of cardiovascular development and disease · 2026Review
- E2F1 Drives Endothelial Arterial Programming in Pulmonary Arterial Hypertension.bioRxiv : the preprint server for biology · 2026Article
- Variation inCirculation research · 2026Article
- Cardiovascular Genetic Epidemiology in the Genome-Wide Era: From Association Discovery to Mechanistic Dissection and Clinical Translation.Cardiovascular drugs and therapy · 2026Review
- Expanding the genetic burden of low-evidence genes in pulmonary arterial hypertension.European journal of human genetics : EJHG · 2026Article
- Identification of drug candidates for rescue of SOX17 gene targets in pulmonary arterial hypertension.bioRxiv : the preprint server for biology · 2026Article
- Experimental pulmonary arterial hypertension in mice with a pathogenic SOX17 variant.Scientific reports · 2026Article
- A blood biomarker to specifically identify idiopathic pulmonary arterial hypertension.Nature cardiovascular research · 2026Article
- Article
- The Role of Genetics in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.Pediatric cardiology · 2026Observational
- Heritable pulmonary arterial hypertension: new genetic findings and environmental triggers.Scientific reports · 2026Article
- Disrupting BMP/TGF-β Signaling: Modulation of AQP1 and TGFB1 in Human Pulmonary Microvascular Endothelial Cells.Comprehensive Physiology · 2025Article
- BMP9 knockout impairs pulmonary vessel muscularisation and confers aberrant tamoxifen sensitivity.Angiogenesis · 2025Article
- Long-term outcomes of Qing-Dai-induced pulmonary arterial hypertension.ERJ open research · 2025Article
170 more citing papers are in PubMed but not listed here.
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Authors and funding
65 authors at 20 institutions in 9 countries.
Stefan GräfDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom. sg550@cam.ac.uk.ORCID http://orcid.org/0000-0002-1315-8873
Matthias HaimelDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.ORCID http://orcid.org/0000-0002-0320-0214
Marta BledaDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.ORCID http://orcid.org/0000-0002-1287-6013
Charaka HadinnapolaDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.ORCID http://orcid.org/0000-0002-7794-3432
Laura SouthgateMolecular and Clinical Sciences Research Institute, St George's, University of London, London, SW17 0RE, United Kingdom.ORCID http://orcid.org/0000-0002-2090-1450
Wei LiDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Joshua HodgsonDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Bin LiuDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Richard M SalmonDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Mark SouthwoodRoyal Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, United Kingdom.
Rajiv D MachadoInstitute of Medical and Biomedical Education, St George's University of London, London, SW17 0RE, United Kingdom.
Jennifer M MartinDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.ORCID http://orcid.org/0000-0002-7697-7438
Carmen M TreacyDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Katherine YatesDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Louise C DaughertyDepartment of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom.
Olga ShamardinaDepartment of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom.ORCID http://orcid.org/0000-0003-4994-2157
Deborah WhitehornDepartment of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom.
Simon HoldenAddenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom.
Micheala AldredCleveland Clinic, Cleveland, Ohio, 44195, United States.ORCID http://orcid.org/0000-0002-7390-9181
Harm J BogaardVU University Medical Center, Amsterdam, 1007 MB, The Netherlands.
Colin ChurchGolden Jubilee National Hospital, Glasgow, G81 4DY, United Kingdom.
Gerry CoghlanRoyal Free Hospital, London, NW3 2QG, United Kingdom.
Robin CondliffeSheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, S10 2JF, United Kingdom.
Paul A CorrisUniversity of Newcastle, Newcastle, NE1 7RU, United Kingdom.
Cesare DanesinoDepartment of Molecular Medicine, University of Pavia, Pavia, 27100, Italy.
Mélanie EyriesDépartement de génétique, hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités, Paris, 75252, France.
Henning GallUniversity 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), Giessen, 35392, Germany.
Stefano GhioFondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
Hossein-Ardeschir GhofraniUniversity 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), Giessen, 35392, Germany.
J Simon R GibbsNational Heart & Lung Institute, Imperial College London, London, SW3 6LY, United Kingdom.
Barbara GirerdUniversité 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, Paris, 94270, France.
Arjan C HouwelingVU University Medical Center, Amsterdam, 1007 MB, The Netherlands.
Luke HowardImperial College London, London, SW7 2AZ, United Kingdom.
Marc HumbertUniversité 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, Paris, 94270, France.
David G KielySheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, S10 2JF, United Kingdom.
Gabor KovacsLudwig Boltzmann Institute for Lung Vascular Research, Graz, 8010, Austria.
Robert V MacKenzie RossRoyal United Hospitals Bath NHS Foundation Trust, Bath, BA1 3NG, United Kingdom.
Shahin MoledinaGreat Ormond Street Hospital, London, WC1N 3JH, United Kingdom.
David MontaniUniversité 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, Paris, 94270, France.ORCID http://orcid.org/0000-0002-9358-6922
Michael NewnhamDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Andrea OlschewskiLudwig Boltzmann Institute for Lung Vascular Research, Graz, 8010, Austria.
Horst OlschewskiLudwig Boltzmann Institute for Lung Vascular Research, Graz, 8010, Austria.
Andrew J PeacockGolden Jubilee National Hospital, Glasgow, G81 4DY, United Kingdom.
Joanna Pepke-ZabaRoyal Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, United Kingdom.
Inga ProkopenkoImperial College London, London, SW7 2AZ, United Kingdom.ORCID http://orcid.org/0000-0003-1624-7457
Christopher J RhodesImperial College London, London, SW7 2AZ, United Kingdom.ORCID http://orcid.org/0000-0002-4962-3204
Laura ScelsiFondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
Werner SeegerUniversity 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), Giessen, 35392, Germany.
Florent SoubrierDépartement de génétique, hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités, Paris, 75252, France.
Dan F SteinDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.ORCID http://orcid.org/0000-0001-7904-832X
Jay SuntharalingamRoyal United Hospitals Bath NHS Foundation Trust, Bath, BA1 3NG, United Kingdom.
Emilia M SwietlikDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
Mark R ToshnerDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.ORCID http://orcid.org/0000-0002-3969-6143
David A van HeelBlizard Institute, Queen Mary University of London, London, E1 2AT, United Kingdom.ORCID http://orcid.org/0000-0002-0637-2265
Anton Vonk NoordegraafVU University Medical Center, Amsterdam, 1007 MB, The Netherlands.
Quinten WaisfiszVU University Medical Center, Amsterdam, 1007 MB, The Netherlands.
John WhartonImperial College London, London, SW7 2AZ, United Kingdom.ORCID http://orcid.org/0000-0001-8110-2575
Stephen J WortImperial College London, London, SW7 2AZ, United Kingdom.
Willem H OuwehandDepartment of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom.
Nicole SoranzoDepartment of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom.ORCID http://orcid.org/0000-0003-1095-3852
Allan LawrieDepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, S10 2RX, United Kingdom.ORCID http://orcid.org/0000-0003-4192-9505
Paul D UptonDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.ORCID http://orcid.org/0000-0003-2716-4921
Martin R WilkinsImperial College London, London, SW7 2AZ, United Kingdom.
Richard C TrembathDivision of Genetics & Molecular Medicine, King's College London, London, WC2R 2LS, United Kingdom.ORCID http://orcid.org/0000-0003-0550-3400
Nicholas W MorrellDepartment of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom. nwm23@cam.ac.uk.ORCID http://orcid.org/0000-0001-5700-9792
University of Cambridge · GBImperial College London · GBAmsterdam UMC Location Vrije Universiteit Amsterdam · NLGerman Center for Lung Research · DEUniversité Paris-Sud · FRGolden Jubilee National Hospital · GBInserm · FRMedical University of Graz · ATPapworth Hospital · GBPoliclinico San Matteo Fondazione · ITRoyal Hallamshire Hospital · GBRoyal United Hospital Bath NHS Trust · GBSt George's, University of London · GBAddenbrooke's Hospital · GBCleveland Clinic · USGreat Ormond Street Hospital · GBKing's College London · GBLudwig Boltzmann Institute for Lung Vascular Research · ATNewcastle University · GBQueen Mary University of London · GB
Funding
Germline and Somatic Genetic Changes in Pulmonary Arterial HypertensionR01HL098199 · NHLBI · INDIANA UNIVERSITY INDIANAPOLIS · PI ALDRED, MICHEALA A · 2010 to 2017
$2.3MBritish Heart Foundation FS/13/48/30453British Heart Foundation FS/15/59/31839British Heart Foundation FS/18/52/33808British Heart Foundation PG/12/54/29734British Heart Foundation PG/15/39/31519British Heart Foundation PG/17/1/32532British Heart Foundation PG/17/58/33134British Heart Foundation RG/13/4/30107British Heart Foundation SP/12/12/29836Medical Research Council MR/K020919/1NHLBI NIH HHS R01 HL098199Wellcome Trust
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.
Indexed as
MutationAdenosine TriphosphatasesAdultAquaporin 1Base SequenceBone Morphogenetic Protein Receptors, Type IICase-Control StudiesFamilial Primary Pulmonary HypertensionFemaleGene Expression RegulationGenetic Predisposition to DiseaseGrowth Differentiation Factor 2Growth Differentiation FactorsHEK293 CellsHumansMaleAdenosine TriphosphatasesAQP1 protein, humanAquaporin 1ATP13A3 protein, humanBMPR2 protein, humanBone Morphogenetic Protein Receptors, Type IIGDF2 protein, humanGrowth Differentiation Factor 2Growth Differentiation FactorsMembrane Transport ProteinsSOX17 protein, humanSOXF Transcription FactorsTransforming Growth Factor beta
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