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Cambridge Cardiovascular



My group's research ambition is to characterise the underlying dysregulated molecular networks of rare vasculopathies like pulmonary arterial hypertension (PAH, high blood pressure in the lungs) through computational integration of genetic and other 'omic data layers. With this, we aim to advance precision genomic medicine.

At the beginning of this century, two independent groups discovered mutations in the bone morphogenetic protein receptor type II (BMPR2) gene, a transforming growth factor beta (TGFß) cell surface receptor that increases the risk of developing pulmonary arterial hypertension (PAH). Since then, additional disease-causing genetic variation has been identified in genes belonging to the TGFß/BMP-signalling pathways (i.e. ACVRL1 (ALK1), ENG, SMAD9) and more recently also in genes not directly associated with these molecular pathways (i.e. CAV1, KCNK3 (TASK1), EIF2AK4 (GCN2)).

The recent focus of my group has been the sequencing of more than a thousand whole genomes of adults and children diagnosed with PAH as part of the NIHR BioResource – a whole-genome sequencing (WGS) project for Rare Diseases. In order to maximise the number of available patients with this rare condition all PAH specialist centres across the UK have formed a national consortium, the National Cohort Study of Idiopathic and Heritable PAH, for patient enrolment, sample collection, and in-depth phenotype capture. To investigate the genotype-phenotype relationship of both the protein-coding and non-coding fraction of the genome, the data integration and genome-wide association is enriched by additional functional multi-omics annotation derived from blood outgrowth endothelial cells (BOECs) in collaboration with the Blueprint Project and other consortium partners.

My group's work also covers the implementation of infrastructure solutions to support the necessary logistics of these large-scale projects as well as the development of new bioinformatics approaches to process and analyse the vast amount of data generated by these high-throughput screens, i.e. exploring big data solutions using the Hadoop framework. On these topics, we are closely collaborating with the University of Cambridge High-Performance Computing Service (HPCS).


Key publications: 

Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension. Swietlik EM, Greene D, Zhu N, Megy K, Cogliano M, Rajaram S, Pandya D, Tilly T, Lutz KA, Welch CCL, Pauciulo MW, Southgate L, Martin JM, Treacy CM, Bogaard HJ, Church C, Coghlan G, Coleman AW, Condliffe R, Eyries M, Gall H, Ghio S, Girerd B, Holden S, Howard L, Humbert M, Kiely DG, Kovacs G, Lordan J, Machado RD, MacKenzie Ross RV, Moledina S, Montani D, Olschewski H, Pepke-Zaba J, Rhodes CJ, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Vonk Noordegraaf A, Wharton J, Wild J, Wort SJ, NIHR BioResource for Translational Research - Rare Diseases, National Cohort Study of Idiopathic and Heritable PAH, PAH Biobank Enrolling Centers’ Investigators, Lawrie A, Wilkins MR, Trembath RC, Shen Y, Chung WK, Swift AJ, Nichols WC, Morrell NW, Gräf SCirc Genom Precis Med. 2020 Dec 15.

Whole-genome sequencing of patients with rare diseases in a national health system. Turro E, Astle WJ, Megy K, Gräf S, Greene D, Shamardina O, Allen HL, Sanchis-Juan A, Frontini M, Thys C, Stephens J, Mapeta R, Burren OS, Downes K, Haimel M, Tuna S, Deevi SVV, Aitman TJ, Bennett DL, Calleja P, Carss K, Caulfield MJ, Chinnery PF, Dixon PH, Gale DP, James R, Koziell A, Laffan MA, Levine AP, Maher ER, Markus HS, Morales J, Morrell NW, Mumford AD, Ormondroyd E, Rankin S, Rendon A, Richardson S, Roberts I, Roy NBA, Saleem MA, Smith KGC, Stark H, Tan RYY, Themistocleous AC, Thrasher AJ, Watkins H, Webster AR, Wilkins MR, Williamson C, Whitworth J, Humphray S, Bentley DR; NIHR BioResource for the 100,000 Genomes Project, Kingston N, Walker N, Bradley JR, Ashford S, Penkett CJ, Freson K, Stirrups KE, Raymond FL, Ouwehand WH. Nature. 2020 Jul;583(7814):96-102.

‘There and back again’ - forward genetics and reverse phenotyping in pulmonary arterial hypertension. Swietlik EM, Prapa M, Martin JM, Pandya D, Auckland K, Morrell NW, Gräf S. Genes2020 Nov 26;11(12):E1408.

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. 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, Suntharalingam J, Swietlik EM, Toshner MR, van Heel DA, Vonk Noordegraaf A, Waisfisz Q, Wharton J, Wort SJ, Ouwehand WH, Soranzo N, Lawrie A, Upton PD, Wilkins MR, Trembath RC, Morrell NW. Nat Commun. 2018 Apr 12;9(1):1416.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension. Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmüller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs S, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado R, MacKenzie Ross R, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner M, Trembath R, Vonk Noordegraaf A, Wilkins MR, Wort SJ, Wharton J; NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH, Gräf S, Morrell NW. Circulation. 2017 Nov 21;136(21):2022-2033.

HGVA: the Human Genome Variation Archive. Lopez J, Coll J, Haimel M, Kandasamy S, Tarraga J, Furio-Tari P, Bari W, Bleda M, Rueda A, Gräf S, Rendon A, Dopazo J, Medina I. Nucleic Acids Res. 2017 Jul 3;45(W1):W189-W194.

Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension. Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JS, Lawrie A, Gräf S, Morrell NW, Wilkins MR. Circulation. 2017 Jan 31;135(5):460-475.

Genome-wide identification and characterisation of human DNA replication origins by initiation site sequencing (ini-seq). Langley AR*, Gräf S*, Smith JC, Krude T. Nucleic Acids Res. 2016 Dec 1;44(21):10230-10247.

Towards a molecular classification of pulmonary arterial hypertension. Gräf S, Morrell NW. Eur Respir J. 2016 Oct;48(4):987-989.

BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Evans JD, Girerd B, Montani D, Wang XJ, Galiè N, Austin ED, Elliott G, Asano K, Grünig E, Yan Y, Jing ZC, Manes A, Palazzini M, Wheeler LA, Nakayama I, Satoh T, Eichstaedt C, Hinderhofer K, Wolf M, Rosenzweig EB, Chung WK, Soubrier F, Simonneau G, Sitbon O, Gräf S, Kaptoge S, Di Angelantonio E, Humbert M, Morrell NW. Lancet Respir Med. 2016 Feb;4(2):129-37.

Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Machado RD, Southgate L, Eichstaedt CA, Aldred MA, Austin ED, Best DH, Chung WK, Benjamin N, Elliott CG, Eyries M, Fischer C, Gräf S, Hinderhofer K, Humbert M, Keiles SB, Loyd JE, Morrell NW, Newman JH, Soubrier F, Trembath RC, Viales RR, Grünig E. Hum Mutat. 2015 Dec;36(12):1113-27.

Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Long L, Ormiston ML, Yang X, Southwood M, Gräf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore SD, Drake KM, Aldred MA, Yu PB, Upton PD, Morrell NW. Nat Med. 2015 Jul;21(7):777-85.

Principal Research Associate


Person keywords: 
rare diseases
genetic variation
pulmonary hypertension
network modelling
machine learning
pulmonary arterial hypertension