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Am J Hum Genet. 2016 Aug 4;99(2):481-8. doi: 10.1016/j.ajhg.2016.06.016.

Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.

Author information

1
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
2
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 Berlin, Berlin 13353, Germany.
3
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
5
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
6
Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA 98195, USA.
7
Department of Neurology, School of Medicine, Boston University, Boston, MA 02118, USA.
8
School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA.
9
Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
10
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
11
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
12
Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
13
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
14
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
15
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.
16
Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
17
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
18
College of Public Health, the University of Iowa, Iowa City, IA 52242, USA.
19
Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
20
Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
21
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
22
Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere 33521, Finland.
23
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.
24
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden RC 2300, the Netherlands.
25
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.
26
Montreal Heart Institute and Université de Montréal, Montreal, QC H1T 1C8, Canada.
27
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
28
Center for Public Health Genomics, University of Virginia, Charlottesville VA 22908, USA.
29
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS 39216, USA.
30
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.
31
Departments of Medicine and Biostatistics, Schools of Medicine and Public Health, Boston University, Boston, MA 02118, USA.
32
Cardiovascular Epidemiology and Human Genomics Branch, Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
33
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
34
Bloodworks Northwest, Seattle, WA 98102, USA.
35
Women's Health Initiative Clinical Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
36
Division of Cardiovascular Medicine, Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
37
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. Electronic address: sankaran@broadinstitute.org.

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.

PMID:
27486782
PMCID:
PMC4974169
DOI:
10.1016/j.ajhg.2016.06.016
[Indexed for MEDLINE]
Free PMC Article

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