. 2016 Nov 17;167(5):1415-1429.e19.

doi: 10.1016/j.cell.2016.10.042.

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

William J Astle¹, Heather Elding², Tao Jiang³, Dave Allen⁴, Dace Ruklisa⁵, Alice L Mann⁶, Daniel Mead⁶, Heleen Bouman⁶, Fernando Riveros-Mckay⁶, Myrto A Kostadima⁷, John J Lambourne⁸, Suthesh Sivapalaratnam⁹, Kate Downes⁸, Kousik Kundu¹⁰, Lorenzo Bomba⁶, Kim Berentsen¹¹, John R Bradley¹², Louise C Daugherty¹³, Olivier Delaneau¹⁴, Kathleen Freson¹⁵, Stephen F Garner⁸, Luigi Grassi⁸, Jose Guerrero⁸, Matthias Haimel¹⁶, Eva M Janssen-Megens¹¹, Anita Kaan¹¹, Mihir Kamat³, Bowon Kim¹¹, Amit Mandoli¹¹, Jonathan Marchini¹⁷, Joost H A Martens¹¹, Stuart Meacham¹³, Karyn Megy¹³, Jared O'Connell¹⁷, Romina Petersen⁸, Nilofar Sharifi¹¹, Simon M Sheard¹⁸, James R Staley³, Salih Tuna¹⁹, Martijn van der Ent¹¹, Klaudia Walter⁶, Shuang-Yin Wang¹¹, Eleanor Wheeler⁶, Steven P Wilder²⁰, Valentina Iotchkova²¹, Carmel Moore³, Jennifer Sambrook²², Hendrik G Stunnenberg¹¹, Emanuele Di Angelantonio²³, Stephen Kaptoge²⁴, Taco W Kuijpers²⁵, Enrique Carrillo-de-Santa-Pau²⁶, David Juan²⁶, Daniel Rico²⁷, Alfonso Valencia²⁶, Lu Chen¹⁰, Bing Ge²⁸, Louella Vasquez⁶, Tony Kwan²⁸, Diego Garrido-Martín²⁹, Stephen Watt⁶, Ying Yang⁶, Roderic Guigo³⁰, Stephan Beck³¹, Dirk S Paul³², Tomi Pastinen²⁸, David Bujold²⁸, Guillaume Bourque²⁸, Mattia Frontini³³, John Danesh³⁴, David J Roberts³⁵, Willem H Ouwehand³⁶, Adam S Butterworth³⁷, Nicole Soranzo³⁸

Affiliations

¹ Department 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.
² 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.
³ 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.
⁴ Blood Research Group, NHS Blood and Transplant, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9BQ, UK.
⁵ Department 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.
⁶ Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
⁷ Department 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.
⁸ Department 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.
⁹ Department 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.
¹⁰ Department 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.
¹¹ Department of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
¹² Department 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.
¹³ Department 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.
¹⁴ Département de Génétique et Développement (GEDEV), University of Geneva, 1211 Geneve 4, Switzerland.
¹⁵ Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
¹⁶ Department 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.
¹⁷ Wellcome 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.
¹⁸ UK Biobank Ltd., 1-4 Spectrum Way, Adswood, Stockport SK3 0SA, UK.
¹⁹ Department 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.
²⁰ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
²¹ Department 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.
²² Department 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.
²³ 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; 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.
²⁴ 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; 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.
²⁵ Emma 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.
²⁶ Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
²⁷ Structural 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.
²⁸ Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
²⁹ Bioinformatics 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.
³⁰ Bioinformatics 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.
³¹ UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
³² 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; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
³³ Department 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.
³⁴ 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; 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.
³⁵ Radcliffe 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.
³⁶ Department 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.
³⁷ 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; 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.
³⁸ Department 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.

PMID: 27863252
PMCID: PMC5300907
DOI: 10.1016/j.cell.2016.10.042

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

William J Astle et al. Cell. 2016.

. 2016 Nov 17;167(5):1415-1429.e19.

doi: 10.1016/j.cell.2016.10.042.

Authors

Affiliations

¹ Department 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.
² 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.
³ 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.
⁴ Blood Research Group, NHS Blood and Transplant, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9BQ, UK.
⁵ Department 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.
⁶ Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
⁷ Department 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.
⁸ Department 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.
⁹ Department 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.
¹⁰ Department 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.
¹¹ Department of Molecular Biology, Radboud University, Faculty of Science, Nijmegen 6525GA, the Netherlands.
¹² Department 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.
¹³ Department 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.
¹⁴ Département de Génétique et Développement (GEDEV), University of Geneva, 1211 Geneve 4, Switzerland.
¹⁵ Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
¹⁶ Department 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.
¹⁷ Wellcome 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.
¹⁸ UK Biobank Ltd., 1-4 Spectrum Way, Adswood, Stockport SK3 0SA, UK.
¹⁹ Department 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.
²⁰ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
²¹ Department 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.
²² Department 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.
²³ 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; 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.
²⁴ 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; 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.
²⁵ Emma 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.
²⁶ Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
²⁷ Structural 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.
²⁸ Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
²⁹ Bioinformatics 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.
³⁰ Bioinformatics 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.
³¹ UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
³² 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; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
³³ Department 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.
³⁴ 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; 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.
³⁵ Radcliffe 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.
³⁶ Department 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.
³⁷ 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; 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.
³⁸ Department 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.

PMID: 27863252
PMCID: PMC5300907
DOI: 10.1016/j.cell.2016.10.042

Abstract

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.

Keywords: Mendelian randomization; autoimmune diseases; blood; cardiovascular diseases; complex disease; epigenetics; genetics; hematology; hematopoiesis.

PubMed Disclaimer

Figures

**Figure 1**
Study Design for GWAS of Complete Blood Count Indices The phenotypes and their classification by hematopoietic cell type; the study sample sizes; and a summary of the analysis methods employed to identify associated loci. Blood cell index names are defined in Table S1. See also Figures S1 and S2.

**Figure 2**
Summary of Genetic Associations with the 36 Blood Cell Indices A Manhattan plot summarizing genome-wide phenotypic associations over 36 indices. Each dot corresponds to a variant. Its x coordinate represents its genomic position and its y coordinate represents the maximum -log₁₀ (p value) for association over all phenotypes. Variants with -log₁₀ (p value) <6 have been removed for clarity. The yellow horizontal line at p = 8.31 × 10⁻⁹ represents the GWAS significance threshold. Sentinel variants are colored green if their associations (or associations with their proxies) have been previously reported and are colored red otherwise. See also Table S3.

**Figure 3**
Distribution of Genetic Effects and Variant Consequences (A) Number of conditionally independent genetic associations categorized by blood cell index and by MAF range. (B) Summary of sizes of subsets of sentinel variants categorized by cell types of associated indices, showing that most associations are cell-type-specific. Each bar counts the number of sentinel variants associated with and only with the blood index class(es) shown. (mRBC, Mature RBC; iRBC, Immature RBC; Lymph, Lymphoid WBC; Comp, Compound WBC; All, Intersection of all blood index classes. “Other” counts variants uncounted by the other bars.) See Table S1 for blood index classification. (C) Bar plot showing the proportions of variants categorized by VEP consequence stratified by derived allele frequency (DAF) range. (D and E) Violin plots showing the distribution of the absolute value of the estimated effect size stratified by VEP impact categories (D) or cell-matched chromatin segmentation states (E). p values correspond to Mann-Whitney-Wilcoxon tests comparing the distributions indicated. See also Table S4.

**Figure 4**
Allelic Architecture of Blood Cell Indices (A) Scatterplot showing the relationship between estimated derived allele frequency (DAF) and the absolute value of the estimated effect size for the sentinel variants. The inset gives the same plot on the logit/log scales. Only associations annotated with an ancestral allele are shown. (B) Scatterplot of LD score estimated heritability (due to common variants) against the (unadjusted) phenotypic variance explained by the conditionally significant variants in a multiple regression model, colored according to index type. (C) A barplot showing the LD score estimated heritability due to common variants (upper limit of gray bars) and the distribution of the unadjusted proportion of phenotypic variance explained (R²) by the conditionally significant variants grouped by genomic location (range of color fills). (D) The same plot for variants grouped by cell-matched chromatin segmentation states. See also Table S4.

**Figure 5**
Enrichment of Trait Associations within Regulatory Regions Odds ratios (bar heights) and 95% confidence intervals (whiskers) for enrichment of blood-index associations with chromatin segmentation states from blood cells. P values for significance are obtained from a generalized linear model, modeling a threshold on the GWAS test statistic as a Bernoulli response while controlling for MAF, distance from gene, and number of LD proxies. The cell types are shown from left to right in each block as follows: megakaryocyte (i.e., the platelet progenitor, purple), erythroblast (i.e., the red cell progenitor, red), monocyte (orange), eosinophil (orange), neutrophil (orange), naive B cell (light blue), and T cell (light blue). See also Table S4.

**Figure 6**
Colocalization between Cellular and Molecular Traits (A) Illustrates the models tested using SMR, as well as the number of variants that were significant for both the cellular and molecular trait at a p value threshold of 8.4 × 10⁻⁶ that show colocalization (P_HEIDI > 0.05) between the cellular and the molecular trait and the overlap of colocalized marks between the four marks across the three cell types. (B and C) Regional plots for the colocalization result in the (B) *JAZF1*, (C) *SLC22A5I* and *GSDMB* loci for monocytes and T cells. The gray squares represent the p value distribution for the corresponding (monocyte and lymphocyte) blood cell index. The black triangles represent the GWAS variant that colocalizes with the eQTL (pink diamond), hQTL (light blue diamonds), and sQTL (gold diamond). The dark blue diamonds represent QTL in the region that do not show colocalization. The crosses represent the regional QTL p value distribution. See also Table S6.

**Figure 7**
Causal Associations with Common Diseases (A–C) A forest plot showing the results of the multivariable Mendelian randomization (MR) analysis conducted on 13 blood cell indices versus fourteen common diseases. Colored diamonds represent the significant trait-disease association at our Bonferroni corrected p value threshold of 2.7 × 10⁻⁴ with uncolored circles denoting non-significant results. Each diamond/circle represents the estimated unconfounded causal odds ratio of disease risk per SD increase of the blood cell index, adjusted for all other blood cell indices tested. The size of the shape is inversely proportional to the SE and the whiskers denote 95% confidence intervals. Forest plots are presented for (A) platelet indices, (B) immature and mature red cell indices, and (C) myeloid and lymphoid white cell indices. See also Table S7.

**Figure S1**
Adjustment for Technical Covariates Affecting Full Blood Count Measurements, Related to Figure 1, Tables S1 and S2, and the STAR Methods (A) Day averaged measurements of MCV taken from a single instrument over the course of UK Biobank baseline recruitment. The discontinuities may have been generated by calibration of the machine against a variable deterministically related to MCV. Continuous drift is visible within some of the piecewise continuous segments. The left plot is obtained using the raw data while the right plot is obtained using the technically adjusted trait, showing elimination of discontinuities and drift. (B) The effect of the time of day of acquisition on the average measurement of MONO%. Data are taken from a single Coulter instrument over the full UK Biobank baseline recruitment period. The left plot is obtained using the raw data while the right plot is obtained using the technically adjusted trait, showing elimination of the dependence of the mean of MONO% on time of day. (C) Example of the effect of time delay between venipuncture and acquisition on the measurement of the mean white blood cell count. Each point gives the average WBC# for samples acquired during baseline UK Biobank recruitment on a single Coulter instrument during a fifteen minute delay interval. The boundaries of the shaded region interpolate the 95% confidence intervals of the means. The left plot is obtained using the raw data while the right plot is obtained using the WBC# trait data that has been adjusted for the technical covariates. The dependence of the mean cell count on delay time has been eliminated. (D) Percentages of the variance of each UK Biobank measured variable explained by the adjustment for technical covariates and seasonal drift on the relevant adjustment scale. Integer labels show the effective number of additional samples gained from making the technical adjustments, meaning the expected number of additional samples that would be required to obtain equivalent p values in a GWAS for the trait if the adjustment were not made. (E) As for (D) except for INTERVAL.

**Figure S2**
Adjustments for Sex and for Biological and Environmental Covariates Affecting Full Blood Count Measurements, Related to Figure 1, Tables S1 and S2, and the STAR Methods (A) The dependence of mean neutrophil count on sex and menopause status in the UK Biobank data adjusted for technical effects. The top plot is obtained using the raw data while the bottom plot is obtained adjusting the data for menopause and sex effects showing the elimination of the variance these covariates explain. (B) Day averaged measurements of neutrophil count taken from a single instrument over the course of the UK Biobank baseline recruitment. There is a long run upward drift in the average count over time. Seasonal oscillation in the average counts is also visible. The top plot is obtained using the raw data while the bottom plot is obtained using the technically adjusted data, showing the elimination of drift and seasonal oscillation. (C) Percentage of variance of UK Biobank traits explained (on the relevant adjustment scale) by sex and covariates affecting full blood counts, including age, menopausal status, smoking and alcohol variables. (D) As for (C) except for INTERVAL traits. (E) Illustration of the method used to determine the weight of evidence that heterogeneity in effect sizes across the three studies exceeded a tolerance criterion. The axes represent effect sizes in UK Biobank, INTERVAL and UK BiLEVE. The black dot represents the vector of study specific effect size estimates ( $\hat{β}$ _{UK Biobank,} $\hat{β}$ _INTERVAL, $\hat{β}$ _{UK BiLEVE,}) for a variant. If the dot lies inside the infinite yellow double-pyramid (defined by three planes intersecting the origin, each normal to one of n₁ = (1,−1/4, −1/4), n₂ = (−1/4,1, −1/4), n₃ = (−1/4,−1/4, 1)) we consider that there is no evidence of between study heterogeneity. If the black dot lies outside the yellow double-pyramid we measure the strength of evidence for heterogeneity as the distance between the black dot and the nearest point on the surface of the pyramid (red dot), with distances scaled to account for the standard errors of the study specific estimators. The nearest point on the pyramid is thus defined as the point in the smallest confidence surface for the estimators that intersects the pyramid (blue ellipsoid). We thresholded the distance score at 5.2 and filtered all variant-blood index pairs exceeding the score from further analysis.

**Figure S3**
Quality Control of Genetic Data for UK Biobank, UK BiLEVE, and INTERVAL, Related to the STAR Methods Workflow describing QC steps for genotypic datasets. Detailed description of QC can be found in the STAR Methods and on the UK Biobank website (http://biobank.ctsu.ox.ac.uk/crystal/refer.cgi?id=155580). (A) INTERVAL samples. (B) UK Biobank + UK BiLEVE samples.

See this image and copyright information in PMC

Comment in

Concerted Genetic Function in Blood Traits.
Kim-Hellmuth S, Lappalainen T. Kim-Hellmuth S, et al. Cell. 2016 Nov 17;167(5):1167-1169. doi: 10.1016/j.cell.2016.10.055. Cell. 2016. PMID: 27863238

References

1. Abraham G., Inouye M. Fast principal component analysis of large-scale genome-wide data. PLoS ONE. 2014;9:e93766. - PMC - PubMed
1. Adams P.C., Reboussin D.M., Barton J.C., McLaren C.E., Eckfeldt J.H., McLaren G.D., Dawkins F.W., Acton R.T., Harris E.L., Gordeuk V.R., Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators Hemochromatosis and iron-overload screening in a racially diverse population. N. Engl. J. Med. 2005;352:1769–1778. - PubMed
1. Asleh R., Guetta J., Kalet-Litman S., Miller-Lotan R., Levy A.P. Haptoglobin genotype- and diabetes-dependent differences in iron-mediated oxidative stress in vitro and in vivo. Circ. Res. 2005;96:435–441. - PubMed
1. 1000 Genomes Project Consortium. Auton A., Brooks L.D., Durbin R.M., Garrison E.P., Kang H.M., Korbel J.O., Marchini J.L., McCarthy S., McVean G.A., Abecasis G.R. A global reference for human genetic variation. Nature. 2015;526:68–74. - PMC - PubMed
1. Boatman S., Barrett F., Satishchandran S., Jing L., Shestopalov I., Zon L.I. Assaying hematopoiesis using zebrafish. Blood Cells Mol. Dis. 2013;51:271–276. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Affiliations

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical