The Polygenic and Monogenic Basis of Blood Traits and Diseases

Dragana Vuckovic; Erik L Bao; Parsa Akbari; Caleb A Lareau; Abdou Mousas; Tao Jiang; Ming-Huei Chen; Laura M Raffield; Manuel Tardaguila; Jennifer E Huffman; Scott C Ritchie; Karyn Megy; Hannes Ponstingl; Christopher J Penkett; Patrick K Albers; Emilie M Wigdor; Saori Sakaue; Arden Moscati; Regina Manansala; Ken Sin Lo; Huijun Qian; Masato Akiyama; Traci M Bartz; Yoav Ben-Shlomo; Andrew Beswick; Jette Bork-Jensen; Erwin P Bottinger; Jennifer A Brody; Frank J A van Rooij; Kumaraswamy N Chitrala; Peter W F Wilson; Hélène Choquet; John Danesh; Emanuele Di Angelantonio; Niki Dimou; Jingzhong Ding; Paul Elliott; Tõnu Esko; Michele K Evans; Stephan B Felix; James S Floyd; Linda Broer; Niels Grarup; Michael H Guo; Qi Guo; Andreas Greinacher; Jeff Haessler; Torben Hansen; Joanna M M Howson; Wei Huang; Eric Jorgenson; Tim Kacprowski; Mika Kähönen; Yoichiro Kamatani; Masahiro Kanai; Savita Karthikeyan; Fotios Koskeridis; Leslie A Lange; Terho Lehtimäki; Allan Linneberg; Yongmei Liu; Leo-Pekka Lyytikäinen; Ani Manichaikul; Koichi Matsuda; Karen L Mohlke; Nina Mononen; Yoshinori Murakami; Girish N Nadkarni; Kjell Nikus; Nathan Pankratz; Oluf Pedersen; Michael Preuss; Bruce M Psaty; Olli T Raitakari; Stephen S Rich; Benjamin A T Rodriguez; Jonathan D Rosen; Jerome I Rotter; Petra Schubert; Cassandra N Spracklen; Praveen Surendran; Hua Tang; Jean-Claude Tardif; Mohsen Ghanbari; Uwe Völker; Henry Völzke; Nicholas A Watkins; Stefan Weiss; VA Million Veteran Program; Na Cai; Kousik Kundu; Stephen B Watt; Klaudia Walter; Alan B Zonderman; Kelly Cho; Yun Li; Ruth J F Loos; Julian C Knight; Michel Georges; Oliver Stegle; Evangelos Evangelou; Yukinori Okada; David J Roberts; Michael Inouye; Andrew D Johnson; Paul L Auer; William J Astle; Alexander P Reiner; Adam S Butterworth; Willem H Ouwehand; Guillaume Lettre; Vijay G Sankaran; Nicole Soranzo

doi:10.1016/j.cell.2020.08.008

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.

Authors

Dragana Vuckovic¹, Erik L Bao², Parsa Akbari³, Caleb A Lareau⁴, Abdou Mousas⁵, Tao Jiang⁶, Ming-Huei Chen⁷, Laura M Raffield⁸, Manuel Tardaguila⁹, Jennifer E Huffman¹⁰, Scott C Ritchie¹¹, Karyn Megy¹², Hannes Ponstingl⁹, Christopher J Penkett¹³, Patrick K Albers⁹, Emilie M Wigdor⁹, Saori Sakaue¹⁴, Arden Moscati¹⁵, Regina Manansala¹⁶, Ken Sin Lo⁵, Huijun Qian¹⁷, Masato Akiyama¹⁸, Traci M Bartz¹⁹, Yoav Ben-Shlomo²⁰, Andrew Beswick²¹, Jette Bork-Jensen²², Erwin P Bottinger²³, Jennifer A Brody²⁴, Frank J A van Rooij²⁵, Kumaraswamy N Chitrala²⁶, Peter W F Wilson²⁷, Hélène Choquet²⁸, John Danesh²⁹, Emanuele Di Angelantonio²⁹, Niki Dimou³⁰, Jingzhong Ding³¹, Paul Elliott³², Tõnu Esko³³, Michele K Evans²⁶, Stephan B Felix³⁴, James S Floyd³⁵, Linda Broer³⁶, Niels Grarup²², Michael H Guo³⁷, Qi Guo³⁸, Andreas Greinacher³⁹, Jeff Haessler⁴⁰, Torben Hansen²², Joanna M M Howson⁴¹, Wei Huang⁴², Eric Jorgenson²⁸, Tim Kacprowski⁴³, Mika Kähönen⁴⁴, Yoichiro Kamatani⁴⁵, Masahiro Kanai⁴⁶, Savita Karthikeyan³⁸, Fotios Koskeridis⁴⁷, Leslie A Lange⁴⁸, Terho Lehtimäki⁴⁹, Allan Linneberg⁵⁰, Yongmei Liu⁵¹, Leo-Pekka Lyytikäinen⁴⁹, Ani Manichaikul⁵², Koichi Matsuda⁵³, Karen L Mohlke⁸, Nina Mononen⁴⁹, Yoshinori Murakami⁵⁴, Girish N Nadkarni¹⁵, Kjell Nikus⁵⁵, Nathan Pankratz⁵⁶, Oluf Pedersen²², Michael Preuss¹⁵, Bruce M Psaty⁵⁷, Olli T Raitakari⁵⁸, Stephen S Rich⁵², Benjamin A T Rodriguez⁷, Jonathan D Rosen⁵⁹, Jerome I Rotter⁶⁰, Petra Schubert⁶¹, Cassandra N Spracklen⁶², Praveen Surendran⁶³, Hua Tang⁶⁴, Jean-Claude Tardif⁶⁵, Mohsen Ghanbari⁶⁶, Uwe Völker⁶⁷, Henry Völzke⁶⁸, Nicholas A Watkins⁶⁹, Stefan Weiss⁶⁷; VA Million Veteran Program; Na Cai⁹, Kousik Kundu⁷⁰, Stephen B Watt⁹, Klaudia Walter⁹, Alan B Zonderman²⁶, Kelly Cho⁷¹, Yun Li⁷², Ruth J F Loos¹⁵, Julian C Knight⁷³, Michel Georges⁷⁴, Oliver Stegle⁷⁵, Evangelos Evangelou⁷⁶, Yukinori Okada⁷⁷, David J Roberts⁷⁸, Michael Inouye⁷⁹, Andrew D Johnson⁷, Paul L Auer¹⁶, William J Astle⁸⁰, Alexander P Reiner⁸¹, Adam S Butterworth²⁹, Willem H Ouwehand⁸², Guillaume Lettre⁶⁵, Vijay G Sankaran⁸³, Nicole Soranzo⁸⁴

Affiliations

¹ Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK.
² Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA; Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, 02142, USA.
³ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK; National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK; MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK; Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.
⁴ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁵ Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada.
⁶ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK.
⁷ The Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, 01702, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, 01702, USA.
⁸ Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁹ Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.
¹⁰ Center for Population Genomics, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, 02130, USA.
¹¹ Department of Public Health and Primary Care, Cambridge Baker Systems Genomics Initiative, University of Cambridge, Cambridge, CB1 8RN, UK; Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, VIC 3004, Australia; Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK.
¹² Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK; National Institute for Health Research (NIHR) BioResource, Cambridge University Hospitals, Cambridge, CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0PT, UK.
¹³ National Institute for Health Research (NIHR) BioResource, Cambridge University Hospitals, Cambridge, CB2 0PT, UK; Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK.
¹⁴ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
¹⁵ Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY, 10029, USA.
¹⁶ Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA.
¹⁷ Department of Statistics and Operation Research, University of North Carolina, Chapel Hill, NC, 27599, USA.
¹⁸ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan; Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8581, Japan.
¹⁹ Department of Biostatistics, University of Washington, Seattle, WA, 98101, USA.
²⁰ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 1QU, UK.
²¹ Translational Health Sciences, Musculoskeletal Research Unit, Bristol Medical School, University of Bristol, Bristol, BS10 5NB, UK.
²² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
²³ Hasso-Plattner-Institut, Universität Potsdam, Potsdam, 14469, Germany; Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY, 10029, USA.
²⁴ Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
²⁵ Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, 3015 GE, the Netherlands.
²⁶ Laboratory of Epidemiology and Population Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.
²⁷ Atlanta VA Medical Center, Decatur, GA, 30033, USA.
²⁸ Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA.
²⁹ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, CB10 1SA, UK; National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK; Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB1 8RN, UK.
³⁰ Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, 69008, France; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece.
³¹ Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA.
³² Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK; Imperial Biomedical Research Centre, Imperial College London and Imperial College NHS Healthcare Trust, London, W2 1NY, UK; Medical Research Council Centre for Environment and Health, Imperial College London, London, W2 1PG, UK; UK Dementia Research Institute, Imperial College London, London, WC1E 6BT, UK; Health Data Research UK London, London, W2 1PG, UK.
³³ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
³⁴ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, 17475, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, 17475, Germany.
³⁵ Department of Medicine, University of Washington, Seattle, WA, 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA.
³⁶ Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, 3015 GE, the Netherlands.
³⁷ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁸ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK.
³⁹ Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
⁴⁰ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98101, USA.
⁴¹ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK; Novo Nordisk Research Centre Oxford, Oxford, OX3 7FZ, UK.
⁴² Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute (SITI), Shanghai, 201203, China.
⁴³ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany; Chair of Experimental Bioinformatics, Research Group Computational Systems Medicine, Technical University of Munich, Freising-Weihenstephan, 85354, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, 17475, Germany.
⁴⁴ Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
⁴⁵ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan; Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan.
⁴⁶ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁴⁷ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece.
⁴⁸ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA.
⁴⁹ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
⁵⁰ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, 2000, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
⁵¹ Department of Medicine, Division of Cardiology, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27701, USA.
⁵² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22903, USA.
⁵³ Department of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan.
⁵⁴ Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
⁵⁵ Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, 33521, Finland; Department of Cardiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
⁵⁶ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
⁵⁷ Departments of Epidemiology, University of Washington, Seattle, WA, 98101, USA; Department of Medicine, University of Washington, Seattle, WA, 98101, USA; Department of Health Services, University of Washington, Seattle, WA, 98101, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
⁵⁸ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, 20521, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20521, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland.
⁵⁹ Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁶⁰ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation (formerly Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
⁶¹ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, 02130, USA.
⁶² Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA; Department of Biostatistics and Epidemiology, University of Massachusetts-Amherst, Amherst, MA, 01002, USA.
⁶³ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; Department of Public Health and Primary Care, Rutherford Fund Fellow, University of Cambridge, Cambridge, CB1 8RN, UK.
⁶⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁶⁵ Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, H3T 1J4, Canada.
⁶⁶ Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, 3015 GE, the Netherlands; Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran.
⁶⁷ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, 17475, Germany.
⁶⁸ Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, 17475, Germany.
⁶⁹ National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0PT, UK.
⁷⁰ Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK.
⁷¹ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, 02130, USA; Department of Medicine, Division on Aging, Brigham and Women's Hospital, Boston, MA, 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁷² Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA; Department of Computer Science, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁷³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
⁷⁴ Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège, Liège, B-4000, Belgium.
⁷⁵ European Bioinformatics Institute, European Molecular Biology Laboratory, Hinxton, CB10 1SA, UK.
⁷⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece.
⁷⁷ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan; Laboratory of Statistical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
⁷⁸ BRC Haematology Theme and Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK; NHSBT Blood and Transplant - Oxford Center, John Radcliffe Hospital, Oxford, OX3 9BQ, UK.
⁷⁹ Department of Public Health and Primary Care, Cambridge Baker Systems Genomics Initiative, University of Cambridge, Cambridge, CB1 8RN, UK; Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, VIC 3004, Australia; Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB1 8RN, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, CB10 1SA, UK; The Alan Turing Institute, London, NW1 2DB, UK.
⁸⁰ MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK; National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0PT, UK.
⁸¹ Department of Epidemiology, University of Washington, Seattle, WA, 98109, USA.
⁸² Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0PT, UK; Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB1 8RN, UK.
⁸³ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Electronic address: sankaran@broadinstitute.org.
⁸⁴ Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK; Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK. Electronic address: ns6@sanger.ac.uk.

Abstract

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Keywords: UK Biobank; blood; chromatin; fine-mapping; genetics; hematopoiesis; omnigenic; polygenic risk; rare disease; splicing.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Female
Gene Regulatory Networks / genetics
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods
Hematopoiesis / genetics
Humans
Male
Multifactorial Inheritance / genetics*
Phenotype
Polymorphism, Single Nucleotide / genetics

Abstract

Publication types

MeSH terms

Grants and funding