Positions: University of Cambridge Professor of Experimental Haematology, Director of Research, Honorary Faculty member Wellcome Sanger Institute, Honorary NHSBT Consultant in Haematology.

Contact: Lindsay Walker; PA to Prof Ouwehand
Email: BGCprojectcoordinator@medschl.cam.ac.uk
Tel: +44 (0) 1223 588183 (NHSBT feature net 48183)

www.bgc.io

Background

The NHS Blood and Transplant (NHSBT) research group, led by Professor Willem H Ouwehand, is embedded in the Department of Haematology at the University of Cambridge. As chair of the Blood transfusion Genomics Consortium he supports a translational research programme which aims to introduce affordable array-based genotyping for blood cell antigens into routine healthcare, not only in the UK but also in other countries participating in the consortium (www.bgc.io). Willem also provides support for the BloodCounts! project (https://www.youtube.com/watch?v=jO61dLWvpN0) which applies machine learning and artificial intelligence to the high-dimensional data generated during the routine full blood count test. His research on rare inherited bleeding, thrombotic and platelet (BPD) disorders is focussed on the role of rare coding and regulatory variants in several BPD genes.

Platelet Biology & Genomics

Platelets are the second most abundant cell in the blood and are produced by fragmentation of megakaryocytes that reside in the bone marrow. Platelets are pivotal to maintain integrity of the vessel wall, acting as a healthy source of factors to the endothelial cell layer that lines our blood vessels.  Conversely, they are poised to respond to signals of vascular damage (e.g. extracellular nucleotides, metabolites, DNA or the collagenous subendothelial matrix) by aggregating and enhancing plasma coagulation.

Individuals with reduced platelet count or function have bleeding tendencies, whereas those with elevated values are at greater risk of heart attacks and stroke.  Interindividual variation in platelet parameters like their function, count, and volume is to a large extent inherited and therefore stable over time.  The principal aim of our research is to identify genetic sequence variants that regulate these parameters, thus highlighting genes required for platelet production and thereby linked to cardiovascular diseases.

To support this endeavour we have established the Cambridge Platelet Function Cohort (PFC) from the Cambridge BioResource. The platelet function of almost 1,000 volunteers in this cohort has been characterised following activation with adenosine 5′-diphosphate or the collagen mimetic CRP-XL.

The PFC has been used to study the production and signaling activity of glycoprotein VI (GPVI) an important platelet receptor for collagen, and for in silico association studies of other genes identified by the Genome Wide Association Scan for platelet count and volume. This revealed that common sequence variation at Chromosome 7q22.3 exerts not only an effect on the volume of platelets but also on their function.

Platelet RNA samples from donors representing the full range of functional responses have also been applied to whole-genome expression arrays, and analysis of this microarray data identified 63 transcript levels that correlated with variation in platelet functional response. In order to determine whether the corresponding genes were important regulators of thrombus formation. COMMD7 and LRRFIP1 were selected for further study based on the observation that common sequence variants in both loci seemed to be associated with the risk of heart attacks in 4235 cases of premature myocardial infarction compared with 6379 controls.

One bottleneck to understanding the genetic controls of platelet function is the development of suitable testing systems. We are developing new ways of measuring platelet activity by a combination of microfluidics and image processing technology.

Overall we believe that by studying sequence variation in human platelet genes, we will add to knowledge of megakaryopoiesis, platelet formation and the quality of platelet transfusions, as well as to pathways targeted by current or future antiplatelet therapy.

Clinical Bioinformatics, Statistical Genetics and Genomics Team

Our team applies statistical and computational methods to discover new genes and molecular mechanisms that control platelet life and function in health and disease. We translate this knowledge into the clinic by developing comprehensive and cost effective DNA tests to improve the diagnosis of inherited bleeding and platelet disorders. Finally we integrate our findings from the gene discovery efforts and from various genome annotation assays (ChIPseq, RNAseq, Riboseq, 4C, HiC, among others) to define the networks of protein-protein interactions and of gene regulation that underpin the lineage commitment and maturation of blood progenitors along the platelet lineage.

Our main projects are:

Thrombogenomics: Streamlining the genetic diagnosis of inherited bleeding and thrombotic disorders under the umbrella of the International Society of Thrombosis and Haemostasis www.thrombogenomics.org.uk.

BRIDGE: Exome and whole genome sequencing to identify the genetic basis of rare diseases with emphasis on cardiovascular disorders bridgestudy.medschl.cam.ac.uk.

Genetics of haematological traits: Discovering new gene functions through genome wide association studies of blood indices and elucidating the molecular mechanisms by which sequence variation alters these traits.

Functional genomics and BLUEPRINT: As part of the BLUEPRINT www.blueprint-epigenome.eu consortium we functionally annotate the genomes of all human blood cells and progenitors. Our group focuses on the platelet lineage and its progenitors.

Integration: This knowledge is integrated to improve our understanding of gene regulation and networks.

NIHR BioResource for Rare Disease

Our team is responsible for the enrolment of participants with a rare disease; to form a BioResource for Rare Diseases.

A Rare disease is defined as a condition which has an incidence of less than 5 in 10,000 individuals of the UK population, and thus affects ~3% of the population (http://www.raredisease.org.uk/about-rare-diseases.htm).  The aims of the BioResource for Rare Diseases are:

(a) to reduce the delay in ascertaining a genetic diagnosis for inherited and acquired genetic disorders (including rare cancers), where the genotype causing phenotype is known, by developing NGST-based diagnostic tests covering NHS diagnostically-important genes; such projects can include translational projects on e.g. a subset of diagnostic genes;

(b) to determine the genetic basis of Inherited Rare Diseases, including rare cancers for which the causative locus has hitherto not been identified, but which have potential wider relevance for the common diseases that are the focus of Biomedical Research Centres/Units (BRC/BRU)-funded translational and experimental medicine research.

Recruitment is via participating BRC/BRU/hospitals with specialist interest in rare diseases, and currently the main focus of our study fall into the themes: infection and immunity, rare cancers, neuroscience and cardiovascular disease. Our active studies are:

Bleeding and Platelet Diseases (BPD)  The immediate purpose of this study is to identify the genetic basis of hitherto unresolved bleeding and platelet disorders by exome-sequencing.

Pulmonary Arterial Hypertension (PAH)  The discovery of the range of genetic mutations underlying PAH will provide a more complete picture of the cause of this disease and identify rational targets for new drugs. It will also pave the way towards prevention strategies for this disease and of the prediction of prognosis based on a genetic classification of PAH.

Primary Immune Disorders (PID)  This study focuses on genetic causes of severe immune disorders, also known as Primary ImmunoDeficiencies with the largest category being CVID, but it may also include the “extreme phenotype” of premature and severe autoimmunity.

Specialist Pathology: Evaluating Exomes in Diagnostics (SPEED) to develop more affordable DNA-based tests for the diagnosis of rare diseases for which the gene is known.

Steroid Resistant Nephrotic Syndrome (SRNS) This study will focus on genetic causes Steroid Resistant Nephrotic Syndrome.

Blueprint

The team spearhead the healthy samples collection for the European consortium, Blueprint (http://www.blueprint-epigenome.eu/) by making use of the NIHR Cambridge Bioresource (http://www.cambridgebioresource.org.uk/) volunteers. The aim of this consortium is to generate reference epigenomes for all the cell types present in the blood as part of the International Human Epigenome Consortium (http://ihec-epigenomes.org/).

Additionally, we apply next generation sequencing methods to further our understanding of megakaryocytes and platelet biology.

Our main projects are:

Comparative Transcription Network Biology: megakaryocyte and neuronal cells make shared usage of several transcription factors and we aim to dissect the mechanisms that lead to different developmental outcomes.

GWAS functional follow-up: recent genome wide association studies of blood indices has led to the discovery of several genes involved in megakaryopoiesis and erythropoiesis. We are using cellular biology and next generation sequencing based techniques to elucidate the function of these genes.

Nuclear Architecture and common variants: in collaboration we are using Hi-C and 4C techniques to map regulatory regions and their target genes in a variety of haemopoietic cell types.

INTERVAL

The INTERVAL study is a randomised controlled trial (RCT) in up to 50,000 NHS Blood and Transplant whole-blood donors recruited at the 25 donation centres across England (http://www.blood.co.uk/). Over a period of two years, participants will be randomised to give blood either at their usual donation intervals or more frequently. Current practice is to invite men and women to give whole blood every 12 and 16 weeks, respectively. During INTERVAL men will be randomised to donate every 12, 10 or 8 weeks and women every 16, 14 or 12 weeks. At the end of the study, we will compare the amount of blood donated and assessments of well-being between the different study groups.

The study’s main objectives are to determine:

1. the optimum interval between donations, for men and women, that maximizes blood supply without unacceptably increasing iron deficiency/anaemia and its potential complications;

2. whether blood donation intervals can be tailored to donors on the basis of demographic, haematological, genetic and lifestyle factors.

During the course of the study, additional blood samples will be taken for a full blood count and storage of plasma, serum and DNA. These will be used to measure biomarkers as well as genetic factors. Online questionnaires regarding health, lifestyle and cognitive function will also be collected. A subset of participants will take part in a study of the impact of donation interval on physical activity levels.

Funding

The research in the Ouwehand group is funded by NHS Blood and Transplant, the National Institute for Health Research, the Medical Research Council, the Rosetrees Trust and the International Society on Thrombosis and Haemostasis.

Key publications

A more complete list of publications can be found here.

• Gleadall NS, Veldhuisen B, Gollub J, Butterworth AS, Ord J, Penkett CJ, Timmer TC, Sauer CM, van der Bolt N, Brown N, Brugger K, Dilthey AT, Duarte D, Grimsley K, van den Hurk K, Jongerius JM, Luken J, Megy K, Miflin G, Nelson CS, Prinsze FJ, Sambrook J, Simeoni I, Sweeting M, Thornton N, Trompeter S, Tuna S, Varma T, Walker MR, NIHR BioResource, Danesh J, Roberts DJ, Ouwehand WH, Stirrups KE, Rendon A, Westhoff CM, Di Angelantonio E, van der Schoot CE, Astle WJ, Watkins NA, Lane WJ. Development and validation of a universal blood donor genotyping platform: a multinational prospective study. Blood Adv. 2020 Aug 11; 4(15): 3495–3506. doi: 10.1182/bloodadvances.2020001894.
• Schulman S, El-Darzi E, Florido MH, Friesen M, Merrill-Skoloff G, Brake MA, Schuster CR, Lin L, Westrick RJ, Cowan CA, Flaumenhaft R; NIHR BioResource, Ouwehand WH, Peerlinck K, Freson K, Turro E, Furie B. A coagulation defect arising from heterozygous premature termination of tissue factor. J Clin Invest. 2020 Oct 1;130(10):5302-5312. doi: 10.1172/JCI133780.
• Sims MC, Mayer L, Collins J, Bariana T, Megy K, Lavenu-Bombled C, Seyres D, Kollipara L, Burden F, Greene D, Lee D, Rodriguez-Romera A, Alessi MC, Astle WJ, Bahou W, Bury L, Chalmers E, Da Silva R, De Candia E, Deevi SVV, Farrow S, Gomez K, Grassi L, Greinacher A, Gresele P, Hart DP, Hurtaud MF, Kelly A, Kerr R, Le Quellec S, Leblanc TM, Leinøe EB, Mapeta RP, McKinney H, Michelson AD, Morais S, Nugent DJ, Papadia S, Park SJ, Pasi J, Podda GM, Poon MC, Reed R, Sekhar M, Shalev H, Sivapalaratnam S, Steinberg-Shemer O, Stephens JC, Tait RC, Turro E, Wu JK, Zieger BMH, BioResource N, Kuijpers TW, Whetton AD, Sickmann A, Freson K, Downes K, Erber W, Frontini M, Nurden P, Ouwehand WH, Favier R, Guerrero JA. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome. Blood. 2020 Jul 21:blood.2019004776. doi: 10.1182/blood.2019004776.
• Shovlin CL, Simeoni I, Downes K, Frazer Z, Megy K, Bernabeu Herrero M, Shurr A, Brimley J, Patel D, Kell L, Stephens J, Turbin I, Aldred MA, Penkett C, Ouwehand WH, Jovine L, Turro E. Mutational and phenotypic characterisation of hereditary hemorrhagic telangiectasia. Blood. 2020 Jun 23:blood.2019004560. doi: 10.1182/blood.2019004560.
• Vuckovic D, Bao EL, Akbari P, Lareau CA, Mousas A, Jiang T, Chen MH, Raffield LM, Tardaguila M, Huffman JE, Ritchie SC, Megy K, Ponstingl H, Penkett CJ, Albers PK, Wigdor EM, Sakaue S, Moscati A, Manansala R, Lo KS, Qian H, Akiyama M, Bartz TM, Ben-Shlomo Y, Beswick A, Bork-Jensen J, Bottinger EP, Brody JA, van Rooij FJA, Chitrala KN, Wilson PWF, Choquet H, Danesh J, Di Angelantonio E, Dimou N, Ding J, Elliott P, Esko T, Evans MK, Felix SB, Floyd JS, Broer L, Grarup N, Guo MH, Guo Q, Greinacher A, Haessler J, Hansen T, Howson JMM, Huang W, Jorgenson E, Kacprowski T, Kähönen M, Kamatani Y, Kanai M, Karthikeyan S, Koskeridis F, Lange LA, Lehtimäki T, Linneberg A, Liu Y, Lyytikäinen LP, Manichaikul A, Matsuda K, Mohlke KL, Mononen N, Murakami Y, Nadkarni GN, Nikus K, Pankratz N, Pedersen O, Preuss M, Psaty BM, Raitakari OT, Rich SS, Rodriguez BAT, Rosen JD, Rotter JI, Schubert P, Spracklen CN, Surendran P, Tang H, Tardif JC, Ghanbari M, Völker U, Völzke H, Watkins NA, Weiss S; VA Million Veteran Program, Cai N, Kundu K, Watt SB, Walter K, Zonderman AB, Cho K, Li Y, Loos RJF, Knight JC, Georges M, Stegle O, Evangelou E, Okada Y, Roberts DJ, Inouye M, Johnson AD, Auer PL, Astle WJ, Reiner AP, Butterworth AS, Ouwehand WH, Lettre G, Sankaran VG, Soranzo N. The Polygenic and Monogenic Basis of Blood Traits and Diseases. Cell. 2020 Sep 3;182(5):1214-1231.e11. doi: 10.1016/j.cell.2020.08.008.
• Grassi L, Izuogu OG, Jorge NAN, Seyres D, Bustamante M, Burden F, Farrow S, Farahi N, Martin FJ, Frankish A, Mudge JM, Kostadima M, Petersen R, Lambourne JJ, Rowlston S, Martin-Rendon E, Clarke L, Downes K, Estivill X, Flicek P, Martens JHA, Yaspo ML, Stunnenberg HG, Ouwehand WH, Passetti F, Turro E, Frontini M. Cell type specific novel lncRNAs and circRNAs in the BLUEPRINT haematopoietic transcriptomes atlas. Haematologica. 2020 Jul 23:haematol.2019.238147. doi: 10.3324/haematol.2019.238147.
• Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann F; Primary Immunodeficiency Consortium for the NIHR Bioresource, Lyons PA, Hurles ME, Savic S, Burns SO, Kuijpers TW, Turro E, Ouwehand WH, Thrasher AJ, Smith KGC. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 2020 Jul;583(7814):90-95. doi: 10.1038/s41586-020-2265-1.
• 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. Whole-genome sequencing of patients with rare diseases in a national health system. Nature. 2020 Jul;583(7814):96-102. doi: 10.1038/s41586-020-2434-2.
• Lentaigne C, Greene D, Sivapalaratnam S, Favier R, Seyres D, Thys C, Grassi L, Mangles S, Sibson K, Stubbs M, Burden F, Bordet JC, Armari-Alla C, Erber W, Farrow S, Gleadall N, Gomez K, Megy K, Papadia S, Penkett CJ, Sims MC, Stefanucci L, Stephens JC, Read RJ, Stirrups KE, Ouwehand WH, Laffan MA; NIHR BioResource, Frontini M, Freson K, Turro E. Germline mutations in the transcription factor IKZF5 cause thrombocytopenia. Blood. 2019 Dec 5;134(23):2070-2081. doi: 10.1182/blood.2019000782.
• Downes K, Megy K, Duarte D, Vries M, Gebhart J, Hofer S, Shamardina O, Deevi SVV, Stephens J, Mapeta R, Tuna S, Al Hasso N, Besser MW, Cooper N, Daugherty L, Gleadall N, Greene D, Haimel M, Martin H, Papadia S, Revel-Vilk S, Sivapalaratnam S, Symington E, Thomas W, Thys C, Tolios A, Penkett CJ; NIHR BioResource, Ouwehand WH, Abbs S, Laffan MA, Turro E, Simeoni I, Mumford AD, Henskens YMC, Pabinger I, Gomez K, Freson K. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.
• Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MAK, Black GC, Brennan P, Elliott P, Flinter FA, Floto RA, Houlden H, Irving M, Koziell A, Maher ER, Markus HS, Morrell NW, Newman WG, Roberts I, Sayer JA, Smith KGC, Taylor JC, Watkins H, Webster AR, Wilkie AOM, Williamson C; NIHR BioResource–Rare Diseases; 100,000 Genomes Project–Rare Diseases Pilot, Ashford S, Penkett CJ, Stirrups KE, Rendon A, Ouwehand WH, Bradley JR, Raymond FL, Caulfield M, Turro E, Chinnery PF. Germline selection shapes human mitochondrial DNA diversity. Science. 2019 May 24;364(6442):eaau6520. doi: 10.1126/science.aau6520.
• Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, Burgess S, Jiang T, Paige E, Surendran P, Oliver-Williams C, Kamat MA, Prins BP, Wilcox SK, Zimmerman ES, Chi A, Bansal N, Spain SL, Wood AM, Morrell NW, Bradley JR, Janjic N, Roberts DJ, Ouwehand WH, Todd JA, Soranzo N, Suhre K, Paul DS, Fox CS, Plenge RM, Danesh J, Runz H, Butterworth AS. Genomic atlas of the human plasma proteome. Nature. 2018 Jun;558(7708):73-79. doi: 10.1038/s41586-018-0175-2.
• Mayer L, Jasztal M, Pardo M, Aguera de Haro S, Collins J, Bariana TK, Smethurst PA, Grassi L, Petersen R, Nurden P, Favier R, Yu L, Meacham S, Astle WJ, Choudhary J, Yue WW, Ouwehand WH, Guerrero JA. Nbeal2 interacts with Dock7, Sec16a, and Vac14. Blood. 2018 Mar 1;131(9):1000-1011. doi: 10.1182/blood-2017-08-800359.
• Kilpinen H, Goncalves A, Leha A, Afzal V, Alasoo K, Ashford S, Bala S, Bensaddek D, Casale FP, Culley OJ, Danecek P, Faulconbridge A, Harrison PW, Kathuria A, McCarthy D, McCarthy SA, Meleckyte R, Memari Y, Moens N, Soares F, Mann A, Streeter I, Agu CA, Alderton A, Nelson R, Harper S, Patel M, White A, Patel SR, Clarke L, Halai R, Kirton CM, Kolb-Kokocinski A, Beales P, Birney E, Danovi D, Lamond AI, Ouwehand WH, Vallier L, Watt FM, Durbin R, Stegle O, Gaffney DJ. Common genetic variation drives molecular heterogeneity in human iPSCs. Nature. 2017 Jun 15;546(7658):370-375. doi: 10.1038/nature22403.
• Pleines I, Woods J, Chappaz S, Kew V, Foad N, Ballester-Beltrán J, Aurbach K, Lincetto C, Lane RM, Schevzov G, Alexander WS, Hilton DJ, Astle WJ, Downes K, Nurden P, Westbury SK, Mumford AD, Obaji SG, Collins PW, Delerue F, Ittner LM, Bryce NS, Holliday M, Lucas CA, Hardeman EC, Ouwehand WH, Gunning PW, Turro E, Tijssen MR, Kile BT. Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. J Clin Invest. 2017 Mar 1;127(3):814-829. doi: 10.1172/JCI86154.
• Sivapalaratnam S, Westbury SK, Stephens JC, Greene D, Downes K, Kelly AM, Lentaigne C, Astle WJ, Huizinga EG, Nurden P, Papadia S, Peerlinck K, Penkett CJ, Perry DJ, Roughley C, Simeoni I, Stirrups K, Hart DP, Tait RC, Mumford AD; NIHR BioResource, Laffan MA, Freson K, Ouwehand WH, Kunishima S, Turro E. Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia. Blood. 2017 Jan 26;129(4):520-524. doi: 10.1182/blood-2016-08-732248.
• Di Angelantonio E, Thompson SG, Kaptoge S, Moore C, Walker M, Armitage J, Ouwehand WH, Roberts DJ, Danesh J; INTERVAL Trial Group. Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors. Lancet. 2017 Nov 25;390(10110):2360-2371. doi: 10.1016/S0140-6736(17)31928-1.
• Petersen R, Lambourne JJ, Javierre BM, Grassi L, Kreuzhuber R, Ruklisa D, Rosa IM, Tomé AR, Elding H, van Geffen JP, Jiang T, Farrow S, Cairns J, Al-Subaie AM, Ashford S, Attwood A, Batista J, Bouman H, Burden F, Choudry FA, Clarke L, Flicek P, Garner SF, Haimel M, Kempster C, Ladopoulos V, Lenaerts AS, Materek PM, McKinney H, Meacham S, Mead D, Nagy M, Penkett CJ, Rendon A, Seyres D, Sun B, Tuna S, van der Weide ME, Wingett SW, Martens JH, Stegle O, Richardson S, Vallier L, Roberts DJ, Freson K, Wernisch L, Stunnenberg HG, Danesh J, Fraser P, Soranzo N, Butterworth AS, Heemskerk JW, Turro E, Spivakov M, Ouwehand WH, Astle WJ, Downes K, Kostadima M, Frontini M. Platelet function is modified by common sequence variation in megakaryocyte super enhancers. Nat Commun. 2017 Jul 13;8:16058. doi: 10.1038/ncomms16058.
• Turro E, Greene D, Wijgaerts A, Thys C, Lentaigne C, Bariana TK, Westbury SK, Kelly AM, Selleslag D, Stephens JC, Papadia S, Simeoni I, Penkett CJ, Ashford S, Attwood A, Austin S, Bakchoul T, Collins P, Deevi SV, Favier R, Kostadima M, Lambert MP, Mathias M, Millar CM, Peerlinck K, Perry DJ, Schulman S, Whitehorn D, Wittevrongel C; BRIDGE-BPD Consortium, De Maeyer M, Rendon A, Gomez K, Erber WN, Mumford AD, Nurden P, Stirrups K, Bradley JR, Lucy Raymond F, Laffan MA, Van Geet C, Richardson S, Freson K, Ouwehand WH. (2016) A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Sci Transl Med. 2016 Mar 2;8(328):328ra30.
• Stritt S, Nurden P, Turro E, Greene D, Jansen SB, Westbury SK, Petersen R, Astle WJ, Marlin S, Bariana TK, Kostadima M, Lentaigne C, Maiwald S, Papadia S, Kelly AM, Stephens JC, Penkett CJ, Ashford S, Tuna S, Austin S, Bakchoul T, Collins P, Favier R, Lambert MP, Mathias M, Millar CM, Mapeta R, Perry DJ, Schulman S, Simeoni I, Thys C; BRIDGE-BPD Consortium, Gomez K, Erber WN, Stirrups K, Rendon A, Bradley JR, van Geet C, Raymond FL, Laffan MA, Nurden AT, Nieswandt B, Richardson S, Freson K, Ouwehand WH, Mumford AD. (2016) A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood. 2016 Jun 9;127(23):2903-14.
• Astle WJ, Elding H, Jiang T, Allen D, Ruklisa D, Mann AL, Mead D, Bouman H, Riveros-Mckay F, Kostadima MA, Lambourne JJ, Sivapalaratnam S, Downes K, Kundu K, Bomba L, Berentsen K, Bradley JR, Daugherty LC, Delaneau O, Freson K, Garner SF, Grassi L, Guerrero J, Haimel M, Janssen-Megens EM, Kaan A, Kamat M, Kim B, Mandoli A, Marchini J, Martens JHA, Meacham S, Megy K, O’Connell J, Petersen R, Sharifi N, Sheard SM, Staley JR, Tuna S, van der Ent M, Walter K, Wang SY, Wheeler E, Wilder SP, Iotchkova V, Moore C, Sambrook J, Stunnenberg HG, Di Angelantonio E, Kaptoge S, Kuijpers TW, Carrillo-de-Santa-Pau E, Juan D, Rico D, Valencia A, Chen L, Ge B, Vasquez L, Kwan T, Garrido-Martín D, Watt S, Yang Y, Guigo R, Beck S, Paul DS, Pastinen T, Bujold D, Bourque G, Frontini M, Danesh J, Roberts DJ, Ouwehand WH, Butterworth AS, Soranzo N. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease. Cell. 2016 Nov 17;167(5):1415-1429.e19. doi: 10.1016/j.cell.2016.10.042.
• Javierre BM, Burren OS, Wilder SP, Kreuzhuber R, Hill SM, Sewitz S, Cairns J, Wingett SW, Várnai C, Thiecke MJ, Burden F, Farrow S, Cutler AJ, Rehnström K, Downes K, Grassi L, Kostadima M, Freire-Pritchett P, Wang F; BLUEPRINT Consortium, Stunnenberg HG, Todd JA, Zerbino DR, Stegle O, Ouwehand WH, Frontini M, Wallace C, Spivakov M, Fraser P. Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters. Cell. 2016 Nov 17;167(5):1369-1384.e19. doi: 10.1016/j.cell.2016.09.037.
• Chen L, Kostadima M, Martens JH, Canu G, Garcia SP, Turro E, Downes K, Macaulay IC, Bielczyk-Maczynska E, Coe S, Farrow S, Poudel P, Burden F, Jansen SB, Astle WJ, Attwood A, Bariana T, de Bono B, Breschi A, Chambers JC; BRIDGE Consortium, Choudry FA, Clarke L, Coupland P, van der Ent M, Erber WN, Jansen JH, Favier R, Fenech ME, Foad N, Freson K, van Geet C, Gomez K, Guigo R, Hampshire D, Kelly AM, Kerstens HH, Kooner JS, Laffan M, Lentaigne C, Labalette C, Martin T, Meacham S, Mumford A, Nürnberg S, Palumbo E, van der Reijden BA, Richardson D, Sammut SJ, Slodkowicz G, Tamuri AU, Vasquez L, Voss K, Watt S, Westbury S, Flicek P, Loos R, Goldman N, Bertone P, Read RJ, Richardson S, Cvejic A, Soranzo N, Ouwehand WH, Stunnenberg HG, Frontini M, Rendon A. (2014) Transcriptional diversity during lineage commitment of human blood progenitors. Science, 345(6204):1251033.
• Cvejic A, Haer-Wigman L, Stephens JC, Kostadima M, Smethurst PA, Frontini M, van den Akker E, Bertone P, Bielczyk-Maczyńska E, Farrow S, Fehrmann RS, Gray A, de Haas M, Haver VG, Jordan G, Karjalainen J, Kerstens HH, Kiddle G, Lloyd-Jones H, Needs M, Poole J, Soussan AA, Rendon A, Rieneck K, Sambrook JG, Schepers H, Silljé HHW, Sipos B, Swinkels D, Tamuri AU, Verweij N, Watkins NA, Westra HJ, Stemple D, Franke L, Soranzo N, Stunnenberg HG, Goldman N, van der Harst P, van der Schoot CE, Ouwehand WH, Albers CA. SMIM1 underlies the Vel blood group and influences red blood cell traits. Nat Genet. 2013 May;45(5):542-545. doi: 10.1038/ng.2603.
• Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 2012 Feb 26;44(4):435-9, S1-2. doi: 10.1038/ng.1083.
• Gieger C, Radhakrishnan A, Cvejic A, Tang W, Porcu E, Pistis G, Serbanovic-Canic J, Elling U, Goodall AH, Labrune Y, Lopez LM, Mägi R, Meacham S, Okada Y, Pirastu N, Sorice R, Teumer A, Voss K, Zhang W, Ramirez-Solis R, Bis JC, Ellinghaus D, Gögele M, Hottenga JJ, Langenberg C, Kovacs P, O’Reilly PF, Shin SY, Esko T, Hartiala J, Kanoni S, Murgia F, Parsa A, Stephens J, van der Harst P, Ellen van der Schoot C, Allayee H, Attwood A, Balkau B, Bastardot F, Basu S, Baumeister SE, Biino G, Bomba L, Bonnefond A, Cambien F, Chambers JC, Cucca F, D’Adamo P, Davies G, de Boer RA, de Geus EJ, Döring A, Elliott P, Erdmann J, Evans DM, Falchi M, Feng W, Folsom AR, Frazer IH, Gibson QD, Glazer NL, Hammond C, Hartikainen AL, Heckbert SR, Hengstenberg C, Hersch M, Illig T, Loos RJ, Jolley J, Khaw KT, Kühnel B, Kyrtsonis MC, Lagou V, Lloyd-Jones H, Lumley T, Mangino M, Maschio A, Mateo Leach I, McKnight B, Memari Y, Mitchell BD, Montgomery GW, Nakamura Y, Nauck M, Navis G, Nöthlings U, Nolte IM, Porteous DJ, Pouta A, Pramstaller PP, Pullat J, Ring SM, Rotter JI, Ruggiero D, Ruokonen A, Sala C, Samani NJ, Sambrook J, Schlessinger D, Schreiber S, Schunkert H, Scott J, Smith NL, Snieder H, Starr JM, Stumvoll M, Takahashi A, Tang WH, Taylor K, Tenesa A, Lay Thein S, Tönjes A, Uda M, Ulivi S, van Veldhuisen DJ, Visscher PM, Völker U, Wichmann HE, Wiggins KL, Willemsen G, Yang TP, Hua Zhao J, Zitting P, Bradley JR, Dedoussis GV, Gasparini P, Hazen SL, Metspalu A, Pirastu M, Shuldiner AR, Joost van Pelt L, Zwaginga JJ, Boomsma DI, Deary IJ, Franke A, Froguel P, Ganesh SK, Jarvelin MR, Martin NG, Meisinger C, Psaty BM, Spector TD, Wareham NJ, Akkerman JW, Ciullo M, Deloukas P, Greinacher A, Jupe S, Kamatani N, Khadake J, Kooner JS, Penninger J, Prokopenko I, Stemple D, Toniolo D, Wernisch L, Sanna S, Hicks AA, Rendon A, Ferreira MA, Ouwehand WH, Soranzo N. New gene functions in megakaryopoiesis and platelet formation. Nature. 2011 Nov 30;480(7376):201-8. doi: 10.1038/nature10659.
• Albers CA, Cvejic A, Favier R, Bouwmans EE, Alessi MC, Bertone P, Jordan G, Kettleborough RN, Kiddle G, Kostadima M, Read RJ, Sipos B, Sivapalaratnam S, Smethurst PA, Stephens J, Voss K, Nurden A, Rendon A, Nurden P, Ouwehand WH. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat Genet. 2011 Jul 17;43(8):735-7. doi: 10.1038/ng.885.