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Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.
Polfus, Linda M; Khajuria, Rajiv K; Schick, Ursula M; Pankratz, Nathan; Pazoki, Raha; Brody, Jennifer A; Chen, Ming-Huei; Auer, Paul L; Floyd, James S; Huang, Jie; Lange, Leslie; van Rooij, Frank J A; Gibbs, Richard A; Metcalf, Ginger; Muzny, Donna; Veeraraghavan, Narayanan; Walter, Klaudia; Chen, Lu; Yanek, Lisa; Becker, Lewis C; Peloso, Gina M; Wakabayashi, Aoi; Kals, Mart; Metspalu, Andres; Esko, Tõnu; Fox, Keolu; Wallace, Robert; Franceschini, Nora; Matijevic, Nena; Rice, Kenneth M; Bartz, Traci M; Lyytikäinen, Leo-Pekka; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Li-Gao, Ruifang; Mook-Kanamori, Dennis O; Lettre, Guillaume; van Duijn, Cornelia M; Franco, Oscar H; Rich, Stephen S; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, André G; Wilson, James G; Psaty, Bruce M; Soranzo, Nicole; Dehghan, Abbas; Boerwinkle, Eric; Zhang, Xiaoling.
  • Polfus LM; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • Khajuria RK; Division 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 Berl
  • Schick UM; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Pankratz N; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
  • Pazoki R; Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Brody JA; Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • Chen MH; Department of Neurology, School of Medicine, Boston University, Boston, MA 02118, USA.
  • Auer PL; School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA.
  • Floyd JS; Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • Huang J; Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
  • Lange L; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
  • van Rooij FJ; Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Gibbs RA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Metcalf G; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Muzny D; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Veeraraghavan N; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Walter K; Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
  • Chen L; Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
  • Yanek L; GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Becker LC; GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Peloso GM; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Wakabayashi A; Division 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.
  • Kals M; Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
  • Metspalu A; Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
  • Esko T; Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
  • Fox K; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • Wallace R; College of Public Health, the University of Iowa, Iowa City, IA 52242, USA.
  • Franceschini N; Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
  • Matijevic N; Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • Rice KM; Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • Bartz TM; Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • Lyytikäinen LP; Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
  • Kähönen M; Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere 33521, Finland.
  • Lehtimäki T; Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
  • Raitakari OT; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
  • Li-Gao R; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden RC 2300, the Netherlands.
  • Mook-Kanamori DO; Department 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.
  • Lettre G; Montreal Heart Institute and Université de Montréal, Montreal, QC H1T 1C8, Canada.
  • van Duijn CM; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Franco OH; Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville VA 22908, USA.
  • Rivadeneira F; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Hofman A; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Uitterlinden AG; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Wilson JG; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS 39216, USA.
  • Psaty BM; Cardiovascular 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.
  • Soranzo N; Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
  • Dehghan A; Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
  • Boerwinkle E; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • Zhang X; Departments of Medicine and Biostatistics, Schools of Medicine and Public Health, Boston University, Boston, MA 02118, USA.
Am J Hum Genet ; 99(2): 481-8, 2016 08 04.
Article en En | MEDLINE | ID: mdl-27486782
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Represoras / Análisis Mutacional de ADN / Proteínas Proto-Oncogénicas / Empalme Alternativo / Sitios Genéticos / Exoma / Hematopoyesis Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article
Texto completo
Imprimir
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PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Represoras / Análisis Mutacional de ADN / Proteínas Proto-Oncogénicas / Empalme Alternativo / Sitios Genéticos / Exoma / Hematopoyesis Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article