A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium

Nicole Soranzo; Tim D. Spector; Massimo Mangino; Brigitte Kühnel; Augusto Rendon; Alexander Teumer; Christina Willenborg; Benjamin Wright; Li Chen; Mingyao Li; Perttu Salo; Benjamin F. Voight; Philippa Burns; Roman A. Laskowski; Yali Xue; Stephan Menzel; David Altshuler; John R. Bradley; Suzannah Bumpstead; Mary Susan Burnett; Joseph Devaney; Angela Döring; Roberto Elosua; Stephen E. Epstein; Wendy Erber; Mario Falchi; Stephen F. Garner; Mohammed J.R. Ghori; Alison H. Goodall; Rhian Gwilliam; Hakon H. Hakonarson; Alistair S. Hall; Naomi Hammond; Christian Hengstenberg; Thomas Illig; Inke R. König; Christopher W. Knouff; Ruth McPherson; Olle Melander; Vincent Mooser; Matthias Nauck; Markku S. Nieminen; Christopher J. O'Donnell; Leena Peltonen; Simon C. Potter; Holger Prokisch; Daniel J. Rader; Catherine M. Rice; Robert Roberts; Veikko Salomaa; Jennifer Sambrook; Stefan Schreiber; Heribert Schunkert; Stephen M. Schwartz; Jovana Serbanovic-Canic; Juha Sinisalo; David S. Siscovick; Klaus Stark; Ida Surakka; Jonathan Stephens; John R. Thompson; Uwe Völker; Henry Völzke; Nicholas A. Watkins; George A. Wells; H. Erich Wichmann; David A. Van Heel; Chris Tyler-Smith; Swee Lay Thein; Sekar Kathiresan; Markus Perola; Muredach P. Reilly; Alexandre F.R. Stewart; Jeanette Erdmann; Nilesh J. Samani; Christa Meisinger; Andreas Greinacher; Panos Deloukas; Willem H. Ouwehand; Christian Gieger

doi:10.1038/ng.467

A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium

Nicole Soranzo^*, Tim D. Spector, Massimo Mangino, Brigitte Kühnel, Augusto Rendon, Alexander Teumer, Christina Willenborg, Benjamin Wright, Li Chen, Mingyao Li, Perttu Salo, Benjamin F. Voight, Philippa Burns, Roman A. Laskowski, Yali Xue, Stephan Menzel, David Altshuler, John R. Bradley, Suzannah Bumpstead, Mary Susan BurnettJoseph Devaney, Angela Döring, Roberto Elosua, Stephen E. Epstein, Wendy Erber, Mario Falchi, Stephen F. Garner, Mohammed J.R. Ghori, Alison H. Goodall, Rhian Gwilliam, Hakon H. Hakonarson, Alistair S. Hall, Naomi Hammond, Christian Hengstenberg, Thomas Illig, Inke R. König, Christopher W. Knouff, Ruth McPherson, Olle Melander, Vincent Mooser, Matthias Nauck, Markku S. Nieminen, Christopher J. O'Donnell, Leena Peltonen, Simon C. Potter, Holger Prokisch, Daniel J. Rader, Catherine M. Rice, Robert Roberts, Veikko Salomaa, Jennifer Sambrook, Stefan Schreiber, Heribert Schunkert, Stephen M. Schwartz, Jovana Serbanovic-Canic, Juha Sinisalo, David S. Siscovick, Klaus Stark, Ida Surakka, Jonathan Stephens, John R. Thompson, Uwe Völker, Henry Völzke, Nicholas A. Watkins, George A. Wells, H. Erich Wichmann, David A. Van Heel, Chris Tyler-Smith, Swee Lay Thein, Sekar Kathiresan, Markus Perola, Muredach P. Reilly, Alexandre F.R. Stewart, Jeanette Erdmann, Nilesh J. Samani, Christa Meisinger, Andreas Greinacher, Panos Deloukas, Willem H. Ouwehand, Christian Gieger

^*Corresponding author for this work

454 Citations (Scopus)

Abstract

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

Original language	English
Journal	Nature Genetics
Volume	41
Issue number	11
Pages (from-to)	1182-1190
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.467
Publication status	Published - 01.11.2009

Funding

The Wellcome Trust, EU (HEALTH-F2-2008-ENGAGE, QLG2-CT-2002-01254), National Institute for Health Research of England (NIHR) (TwinsUK); The Wellcome Trust (UKBS-CC1); Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, the German Federal Ministry of Education and Research (BMBF), the German National Genome Research Network (NGFN), Munich Center of Health Sciences (MC Health) (KORA); Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), Ministry of Cultural Affairs, Social Ministry of the Federal State of Mecklenburg-West Pomerania, Deutsche Forschungsgemeinschaft (grant SFB TR 19), the Federal Ministry of Education and Research (grant no. 03ZIK012); a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania (SHIP); NIHR, CBMRC, NHSBT, (CBR); Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Research (BMBF) (NGFN-2 and NGFN-plus), EU (LSHM-CT-2006-037593) (GerMIFS I and II); BHF and the UK MRC, the Wellcome Trust, Leicester NIHR Biomedical Research Unit in Cardiovascular Disease and EU-FP6 (LSHM-CT-2004-503485) (WTCCC-CAD); Cardiovascular Institute (University of Pennsylvania), GlaxoSmithKline, MedSTAR Research Institute (PennCATH/ MedSTAR); US National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (STAMPEED), National Center for Research Resource (U54 RR020278) (MIGen); Canadian Institutes of Health Research (MOP82810, NA6650 and MOP77682), Canada Foundation for Innovation and Ontario Research Foundation (#11966) (OHGS); Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation (COROGENE); Juvenile Diabetes Research Foundation/Wellcome Trust (T1D). 1Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. 2Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. 3Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 4Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge, UK. 5Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany. 6Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. 7Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany. 8Department of Health Sciences, University of Leicester, Leicester, UK. 9John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. 10Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 11Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. 12The Institute of Molecular Medicine, University of Helsinki, Finland. 13Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. 14Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 15European Bioinformatics Institute, Genome Campus, Hinxton, UK. 16Department of Haematology, King’s College London, London, UK. 17Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. 18Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 19Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. 20Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK. 21Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA. 22Cardiovascular Epidemiology and Genetics, Institut Municipal D’investigacio Medica and CIBER Epidemiología y Salud Pública, Barcelona, Spain.23Haematology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 24Section of Genomic Medicine, Imperial College London, South Kensington Campus, London, UK. 25Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. 26The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 27BHF Heart Research Centre, Clinical Cardiology, Leeds General Infirmary, Leeds, UK. 28Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany. 29Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA. 30Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö, Sweden. 31Institut für Klinische Chemie und Laboratoriumsmedizin, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany. 32Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), Helsinki, Finland. 33Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. 34Department of Human Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany. 35Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 36The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 37The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 38Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany. 39Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA. 40Department of Epidemiology, University of Washington, Seattle, Washington, USA. 41Institute for Community Medicine, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany. 42Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität and Klinikum Grosshadern, Munich, Germany. 43Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 44Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany. 45These authors contributed equally to this work. Correspondence should be addressed to N.S. ([email protected]).

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10.1038/ng.467

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Soranzo, N., Spector, T. D., Mangino, M., Kühnel, B., Rendon, A., Teumer, A., Willenborg, C., Wright, B., Chen, L., Li, M., Salo, P., Voight, B. F., Burns, P., Laskowski, R. A., Xue, Y., Menzel, S., Altshuler, D., Bradley, J. R., Bumpstead, S., ... Gieger, C. (2009). A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nature Genetics, 41(11), 1182-1190. https://doi.org/10.1038/ng.467

@article{60df3352075141e2ac88820abe5484f7,

title = "A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium",

abstract = "The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.",

author = "Nicole Soranzo and Spector, \{Tim D.\} and Massimo Mangino and Brigitte K{\"u}hnel and Augusto Rendon and Alexander Teumer and Christina Willenborg and Benjamin Wright and Li Chen and Mingyao Li and Perttu Salo and Voight, \{Benjamin F.\} and Philippa Burns and Laskowski, \{Roman A.\} and Yali Xue and Stephan Menzel and David Altshuler and Bradley, \{John R.\} and Suzannah Bumpstead and Burnett, \{Mary Susan\} and Joseph Devaney and Angela D{\"o}ring and Roberto Elosua and Epstein, \{Stephen E.\} and Wendy Erber and Mario Falchi and Garner, \{Stephen F.\} and Ghori, \{Mohammed J.R.\} and Goodall, \{Alison H.\} and Rhian Gwilliam and Hakonarson, \{Hakon H.\} and Hall, \{Alistair S.\} and Naomi Hammond and Christian Hengstenberg and Thomas Illig and K{\"o}nig, \{Inke R.\} and Knouff, \{Christopher W.\} and Ruth McPherson and Olle Melander and Vincent Mooser and Matthias Nauck and Nieminen, \{Markku S.\} and O'Donnell, \{Christopher J.\} and Leena Peltonen and Potter, \{Simon C.\} and Holger Prokisch and Rader, \{Daniel J.\} and Rice, \{Catherine M.\} and Robert Roberts and Veikko Salomaa and Jennifer Sambrook and Stefan Schreiber and Heribert Schunkert and Schwartz, \{Stephen M.\} and Jovana Serbanovic-Canic and Juha Sinisalo and Siscovick, \{David S.\} and Klaus Stark and Ida Surakka and Jonathan Stephens and Thompson, \{John R.\} and Uwe V{\"o}lker and Henry V{\"o}lzke and Watkins, \{Nicholas A.\} and Wells, \{George A.\} and Wichmann, \{H. Erich\} and \{Van Heel\}, \{David A.\} and Chris Tyler-Smith and Thein, \{Swee Lay\} and Sekar Kathiresan and Markus Perola and Reilly, \{Muredach P.\} and Stewart, \{Alexandre F.R.\} and Jeanette Erdmann and Samani, \{Nilesh J.\} and Christa Meisinger and Andreas Greinacher and Panos Deloukas and Ouwehand, \{Willem H.\} and Christian Gieger",

year = "2009",

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doi = "10.1038/ng.467",

language = "English",

volume = "41",

pages = "1182--1190",

journal = "Nature Genetics",

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publisher = "Nature Research",

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Soranzo, N, Spector, TD, Mangino, M, Kühnel, B, Rendon, A, Teumer, A, Willenborg, C, Wright, B, Chen, L, Li, M, Salo, P, Voight, BF, Burns, P, Laskowski, RA, Xue, Y, Menzel, S, Altshuler, D, Bradley, JR, Bumpstead, S, Burnett, MS, Devaney, J, Döring, A, Elosua, R, Epstein, SE, Erber, W, Falchi, M, Garner, SF, Ghori, MJR, Goodall, AH, Gwilliam, R, Hakonarson, HH, Hall, AS, Hammond, N, Hengstenberg, C, Illig, T, König, IR, Knouff, CW, McPherson, R, Melander, O, Mooser, V, Nauck, M, Nieminen, MS, O'Donnell, CJ, Peltonen, L, Potter, SC, Prokisch, H, Rader, DJ, Rice, CM, Roberts, R, Salomaa, V, Sambrook, J, Schreiber, S, Schunkert, H, Schwartz, SM, Serbanovic-Canic, J, Sinisalo, J, Siscovick, DS, Stark, K, Surakka, I, Stephens, J, Thompson, JR, Völker, U, Völzke, H, Watkins, NA, Wells, GA, Wichmann, HE, Van Heel, DA, Tyler-Smith, C, Thein, SL, Kathiresan, S, Perola, M, Reilly, MP, Stewart, AFR, Erdmann, J, Samani, NJ, Meisinger, C, Greinacher, A, Deloukas, P, Ouwehand, WH & Gieger, C 2009, 'A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium', Nature Genetics, vol. 41, no. 11, pp. 1182-1190. https://doi.org/10.1038/ng.467

TY - JOUR

T1 - A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium

AU - Soranzo, Nicole

AU - Spector, Tim D.

AU - Mangino, Massimo

AU - Kühnel, Brigitte

AU - Rendon, Augusto

AU - Teumer, Alexander

AU - Willenborg, Christina

AU - Wright, Benjamin

AU - Chen, Li

AU - Li, Mingyao

AU - Salo, Perttu

AU - Voight, Benjamin F.

AU - Burns, Philippa

AU - Laskowski, Roman A.

AU - Xue, Yali

AU - Menzel, Stephan

AU - Altshuler, David

AU - Bradley, John R.

AU - Bumpstead, Suzannah

AU - Burnett, Mary Susan

AU - Devaney, Joseph

AU - Döring, Angela

AU - Elosua, Roberto

AU - Epstein, Stephen E.

AU - Erber, Wendy

AU - Falchi, Mario

AU - Garner, Stephen F.

AU - Ghori, Mohammed J.R.

AU - Goodall, Alison H.

AU - Gwilliam, Rhian

AU - Hakonarson, Hakon H.

AU - Hall, Alistair S.

AU - Hammond, Naomi

AU - Hengstenberg, Christian

AU - Illig, Thomas

AU - König, Inke R.

AU - Knouff, Christopher W.

AU - McPherson, Ruth

AU - Melander, Olle

AU - Mooser, Vincent

AU - Nauck, Matthias

AU - Nieminen, Markku S.

AU - O'Donnell, Christopher J.

AU - Peltonen, Leena

AU - Potter, Simon C.

AU - Prokisch, Holger

AU - Rader, Daniel J.

AU - Rice, Catherine M.

AU - Roberts, Robert

AU - Salomaa, Veikko

AU - Sambrook, Jennifer

AU - Schreiber, Stefan

AU - Schunkert, Heribert

AU - Schwartz, Stephen M.

AU - Serbanovic-Canic, Jovana

AU - Sinisalo, Juha

AU - Siscovick, David S.

AU - Stark, Klaus

AU - Surakka, Ida

AU - Stephens, Jonathan

AU - Thompson, John R.

AU - Völker, Uwe

AU - Völzke, Henry

AU - Watkins, Nicholas A.

AU - Wells, George A.

AU - Wichmann, H. Erich

AU - Van Heel, David A.

AU - Tyler-Smith, Chris

AU - Thein, Swee Lay

AU - Kathiresan, Sekar

AU - Perola, Markus

AU - Reilly, Muredach P.

AU - Stewart, Alexandre F.R.

AU - Erdmann, Jeanette

AU - Samani, Nilesh J.

AU - Meisinger, Christa

AU - Greinacher, Andreas

AU - Deloukas, Panos

AU - Ouwehand, Willem H.

AU - Gieger, Christian

PY - 2009/11/1

Y1 - 2009/11/1

N2 - The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

AB - The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

UR - https://www.scopus.com/pages/publications/70350644759

U2 - 10.1038/ng.467

DO - 10.1038/ng.467

M3 - Journal articles

C2 - 19820697

AN - SCOPUS:70350644759

SN - 1061-4036

VL - 41

SP - 1182

EP - 1190

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium

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