ArticleAmerican journal of human genetics2016
Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.
Erratum issuedOpen access · bronzeAbstract read
In one paragraph
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 31 papers, 1 of them a synthesis that pooled it.
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31citing papers in PubMed, 1 pooled it
8.1field-weighted citation impact, top 3% of its field
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it, 59 citations in OpenAlex.
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- In The Blood: Connecting Variant to Function In Human Hematopoiesis.Trends in genetics : TIG · 2020Review
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- Comparative and Functional Genomic Resource for Mechanistic Studies of Human Blood Pressure-Associated Single Nucleotide Polymorphisms.Hypertension (Dallas, Tex. : 1979) · 2020Article
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Corrections and comments
- Erratum issued
Authors and funding
56 authors at 20 institutions in 8 countries.
Linda M PolfusHuman Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Rajiv K KhajuriaDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA,; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, Berlin 13353, Germany.
Ursula M SchickThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nathan PankratzDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
Raha PazokiDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
Jennifer A BrodyCardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Ming-Huei ChenDepartment of Neurology, School of Medicine, Boston University, Boston, MA 02118, USA.
Paul L AuerSchool of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA.
James S FloydCardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Jie HuangHuman Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Leslie LangeDepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Frank J A van RooijDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
Richard A GibbsHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Ginger MetcalfHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Donna MuznyHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Narayanan VeeraraghavanHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Klaudia WalterHuman Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Lu ChenHuman Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
Lisa YanekGeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Lewis C BeckerGeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Gina M PelosoCenter for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Aoi WakabayashiDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA,; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Mart KalsEstonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
Andres MetspaluEstonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
Tõnu EskoEstonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
Keolu FoxDepartment of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Robert WallaceCollege of Public Health, the University of Iowa, Iowa City, IA 52242, USA.
Nora FranceschiniDepartment of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Nena MatijevicDepartment of Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Kenneth M RiceCardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Traci M BartzCardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Leo-Pekka LyytikäinenDepartment of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
Mika KähönenDepartment of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere 33521, Finland.
Terho LehtimäkiDepartment of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
Olli T RaitakariDepartment of Clinical Physiology and Nuclear Medicine, Turku University Hospital and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
Ruifang Li-GaoDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden RC 2300, the Netherlands.
Dennis O Mook-KanamoriDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden RC 2300, the Netherlands; Epidemiology Section, Department of Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211 Saudi Arabia.
Guillaume LettreMontreal Heart Institute and Université de Montréal, Montreal, QC H1T 1C8, Canada.
Cornelia M van DuijnDepartment of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
Oscar H FrancoDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville VA 22908, USA.
Fernando RivadeneiraDepartment of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
Albert HofmanDepartment of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
André G UitterlindenDepartment of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS 39216, USA.
Bruce M PsatyCardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
Nicole SoranzoHuman Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
Abbas DehghanDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
Eric BoerwinkleHuman Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Xiaoling ZhangDepartments of Medicine and Biostatistics, Schools of Medicine and Public Health, Boston University, Boston, MA 02118, USA.
Andrew D JohnsonCardiovascular Epidemiology and Human Genomics Branch, Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
Christopher J O'DonnellFramingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
Jill M JohnsenBloodworks Northwest, Seattle, WA 98102, USA.
Alexander P ReinerWomen's Health Initiative Clinical Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Santhi K GaneshDivision of Cardiovascular Medicine, Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Vijay G SankaranDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA,; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: sankaran@broadinstitute.org.
Erasmus MC · NLUniversity of Washington · USBaylor College of Medicine · USBroad Institute · USThe University of Texas Health Science Center at Houston · USUniversity of Tartu · EEBoston University · USJohns Hopkins University · USLeiden University Medical Center · NLNational Heart Lung and Blood Institute · USTampere University · FIUniversity of Cambridge · GBUniversity of North Carolina at Chapel Hill · USWellcome Sanger Institute · GBBloodworks Northwest · USFred Hutch Cancer Center · USGroup Health Cooperative · USIcahn School of Medicine at Mount Sinai · USJackson Memorial Hospital · USMassachusetts General Hospital · US
Funding
Cardiovascular Genomics and Bioinformatics projectsZIAHL006170 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI JOHNSON, ANDREW · 2013 to 2025
$25.3MSystematic Genetic Dissection of Human ErythropoiesisR01DK103794 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI Vijay Ganesh Sankaran · 2014 to 2026
$5.9MGenetic Studies of The Impact of Hematologic Traits On Cardiovascular DiseaseR01HL122684 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GANESH, SANTHI K · 2015 to 2019
$3.4MIdentifying Genome-wide Association Study-Nominated Regulators of ErythropoiesisR33HL120791 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI SANKARAN, VIJAY GANESH · 2016 to 2018
$1.7MIdentifying Genome-wide Association Study-Nominated Regulators of ErythropoiesisR21HL120791 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI SANKARAN, VIJAY GANESH · 2014 to 2015
$477kNHLBI NIH HHS R01 HL122684NHLBI NIH HHS R21 HL120791NHLBI NIH HHS R33 HL120791NIDDK NIH HHS R01 DK103794Wellcome TrustWellcome Trust WT098051
Abstract
Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis.
Indexed as
DNA Mutational AnalysisAlternative SplicingBlood PlateletsCRISPR-Cas SystemsExomeGene EditingGenetic LociHematopoiesisHematopoietic Stem CellsHumansMegakaryocytesPlatelet CountProto-Oncogene ProteinsRepressor ProteinsGFI1B protein, humanProto-Oncogene ProteinsRepressor Proteins
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