Journal article
Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis
American journal of human genetics, Vol.99(2), pp.481-488
08/04/2016
DOI: 10.1016/j.ajhg.2016.06.016
PMCID: PMC4974169
PMID: 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.
Details
- Title: Subtitle
- Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis
- Creators
- Linda M Polfus - The University of Texas Health Science Center at HoustonRajiv K Khajuria - Charité - Universitätsmedizin BerlinUrsula M Schick - Icahn School of Medicine at Mount SinaiNathan Pankratz - University of MinnesotaRaha Pazoki - Erasmus MCJennifer A Brody - University of WashingtonMing-Huei Chen - Boston UniversityPaul L Auer - University of Wisconsin–MilwaukeeJames S Floyd - University of WashingtonJie Huang - Wellcome Sanger InstituteLeslie Lange - University of North Carolina at Chapel HillFrank J A van Rooij - Erasmus MCRichard A Gibbs - Baylor College of MedicineGinger Metcalf - Baylor College of MedicineDonna Muzny - Baylor College of MedicineNarayanan Veeraraghavan - Baylor College of MedicineKlaudia Walter - Wellcome Sanger InstituteLu Chen - University of CambridgeLisa Yanek - Johns Hopkins UniversityLewis C Becker - Johns Hopkins UniversityGina M Peloso - Harvard UniversityAoi Wakabayashi - Broad InstituteMart Kals - University of TartuAndres Metspalu - University of TartuTõnu Esko - University of TartuKeolu Fox - University of WashingtonRobert Wallace - University of IowaNora Franceschini - University of North Carolina at Chapel HillNena Matijevic - The University of Texas Health Science Center at HoustonKenneth M Rice - University of WashingtonTraci M Bartz - University of WashingtonLeo-Pekka Lyytikäinen - University of TampereMika Kähönen - University of TampereTerho Lehtimäki - University of TampereOlli T Raitakari - Turku University HospitalRuifang Li-Gao - Leiden University Medical CenterDennis O Mook-Kanamori - Leiden University Medical CenterGuillaume Lettre - Montreal Heart InstituteCornelia M van Duijn - Erasmus MCOscar H Franco - Erasmus MCStephen S Rich - University of VirginiaFernando Rivadeneira - Erasmus MCAlbert Hofman - Erasmus MCAndré G Uitterlinden - Erasmus MCJames G Wilson - University of Mississippi Medical CenterBruce M Psaty - Kaiser Permanente Washington Health Research InstituteNicole Soranzo - University of CambridgeAbbas Dehghan - Erasmus MCEric Boerwinkle - The University of Texas Health Science Center at HoustonXiaoling Zhang - Boston UniversityAndrew D Johnson - National Heart Lung and Blood InstituteChristopher J O'Donnell - National Heart Lung and Blood InstituteJill M Johnsen - Bloodworks NorthwestAlexander P Reiner - Fred Hutch Cancer CenterSanthi K Ganesh - University of MichiganVijay G Sankaran - Broad Institute
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.99(2), pp.481-488
- DOI
- 10.1016/j.ajhg.2016.06.016
- PMID
- 27486782
- PMCID
- PMC4974169
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- R01 HL122684 / NHLBI NIH HHS WT098051 / Wellcome Trust R01 DK103794 / NIDDK NIH HHS R33 HL120791 / NHLBI NIH HHS R21 HL120791 / NHLBI NIH HHS
- Language
- English
- Date published
- 08/04/2016
- Academic Unit
- Epidemiology; Injury Prevention Research Center; Internal Medicine
- Record Identifier
- 9984363613002771
Metrics
16 Record Views