The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.
Astle WJDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge CB2 0SR, UK; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Elding HDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Jiang TMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Allen DBlood Research Group, NHS Blood and Transplant, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9BQ, UK.
Ruklisa DDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge CB2 0SR, UK.
Mann ALDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Mead DDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Bouman HDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Riveros-Mckay FDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Kostadima MADepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Lambourne JJDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Sivapalaratnam SDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Department of Haematology, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London, London E1 1BB, UK.
Downes KDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Kundu KDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Bomba LDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Berentsen KDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Bradley JRDepartment of Medicine, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0QQ, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.
Daugherty LCDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Delaneau ODépartement de Génétique et Développement (GEDEV), University of Geneva, 1211 Geneve 4, Switzerland.
Freson KDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
Garner SFDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Grassi LDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Guerrero JDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Haimel MDepartment of Medicine, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0QQ, UK; NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Janssen-Megens EMDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Kaan ADepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Kamat MMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Kim BDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Mandoli ADepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Marchini JWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
Martens JHADepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Meacham SDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Megy KDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
O'Connell JWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
Petersen RDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
Sharifi NDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Staley JRMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Tuna SDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
van der Ent MDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Walter KDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Wang SYDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Wheeler EDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Wilder SPEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Iotchkova VDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Moore CMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Sambrook JDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Stunnenberg HGDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
Di Angelantonio EMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Kaptoge SMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Kuijpers TWEmma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Location H7-230, Meibergdreef 9, Amsterdam 1105AZ, the Netherlands; Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Plesmanlaan 125, Amsterdam, 1066CX, the Netherlands.
Carrillo-de-Santa-Pau EStructural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Juan DStructural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Rico DStructural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain; Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Valencia AStructural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Chen LDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Ge BHuman Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
Vasquez LDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Garrido-Martín DBioinformatics and Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer del Dr. Aiguader, 88, Barcelona 8003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Plaça de la Mercè, 10- 12, Barcelona 8002, Spain.
Watt SDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Yang YDepartment of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Guigo RBioinformatics and Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer del Dr. Aiguader, 88, Barcelona 8003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Plaça de la Mercè, 10- 12, Barcelona 8002, Spain; Computational Genomics, Institut Hospital del Mar d'Investigacions Mediques (IMIM), Carrer del Dr. Aiguader, 88, Barcelona 8003, Spain.
Beck SUCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
Paul DSMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
Frontini MDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Danesh JMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals, Cambridge CB2 0QQ, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address: jd292@medschl.cam.ac.uk.
Roberts DJRadcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK; Department of Haematology, Churchill Hospital, Headington, Oxford OX3 7LE, UK. Electronic address: david.roberts@ndcls.ox.ac.uk.
Ouwehand WHDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address: who1000@cam.ac.uk.
Butterworth ASMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address: asb38@medschl.cam.ac.uk.
Soranzo NDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address: ns6@sanger.ac.uk.
English
Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.