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dc.contributor.authorPaul, Dirk S
dc.contributor.authorAlbers, Cornelis A
dc.contributor.authorRendon, Augusto
dc.contributor.authorVoss, Katrin
dc.contributor.authorStephens, Jonathan
dc.contributor.authorvan der Harst, Pim
dc.contributor.authorChambers, John C
dc.contributor.authorSoranzo, Nicole
dc.contributor.authorOuwehand, Willem H
dc.contributor.authorDeloukas, Panos
dc.date.accessioned2014-08-06T10:21:24Z
dc.date.available2014-08-06T10:21:24Z
dc.date.issued2013-07
dc.date.submitted2013
dc.identifier.citationGenome Res. 2013, 23 (7):1130-41en
dc.identifier.issn1549-5469
dc.identifier.pmid23570689
dc.identifier.doi10.1101/gr.155127.113
dc.identifier.urihttp://hdl.handle.net/2336/324314
dc.descriptionTo access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.en
dc.description.abstractNearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.
dc.description.sponsorshipMarie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051en
dc.description.sponsorshipinfo:eu-repo/grantAgreement/EC/FP7/282510en
dc.language.isoenen
dc.publisherCold Spring Harbor Lab Pressen
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/282510en
dc.relation.urlhttp://dx.doi.org/10.1101/gr.155127.113en
dc.rightsopenAccessen
dc.subject.meshBlood Plateletsen
dc.subject.meshCell Lineageen
dc.subject.meshChromatinen
dc.subject.meshChromatin Assembly and Disassemblyen
dc.subject.meshChromosome Mappingen
dc.subject.meshCluster Analysisen
dc.subject.meshErythrocytesen
dc.subject.meshGene Expression Regulationen
dc.subject.meshGenetic Variationen
dc.subject.meshGenome-Wide Association Studyen
dc.subject.meshHistonesen
dc.subject.meshHumansen
dc.subject.meshMyeloid Cellsen
dc.subject.meshNucleosomesen
dc.subject.meshOrgan Specificityen
dc.subject.meshPhenotypeen
dc.subject.meshPolymorphism, Single Nucleotideen
dc.subject.meshQuantitative Trait Locien
dc.subject.meshQuantitative Trait, Heritableen
dc.subject.meshRegulatory Sequences, Nucleic Aciden
dc.titleMaps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci.en
dc.typeArticleen
dc.contributor.departmentWellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, Englanden
dc.identifier.journalGenome researchen
dc.rights.accessOpen Accessen
refterms.dateFOA2018-09-12T13:28:23Z
html.description.abstractNearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.


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