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Genome Res. 2013 Jul;23(7):1130-41. doi: 10.1101/gr.155127.113. Epub 2013 Apr 9.

Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci.

Collaborators (239)

Akkerman JW, Albers CA, Algra A, Al-Hussani A, Allayee H, Anni F, Asselbergs FW, Attwood A, Balkau B, Bandinelli S, Bastardot F, Basu S, Baumeister SE, Beckmann J, Benyamin B, Biino G, Bis JC, Bomba L, Bonnefond A, Boomsma DI, Bradley JR, Cambien F, Chambers JC, Ciullo M, Cookson WO, Cucca F, Cvejic A, D'Adamo AP, Danesh J, Danjou F, Das D, Davies G, de Bakker PI, de Boer RA, de Geus EJ, Deary IJ, Dedoussis GV, Deloukas P, Dimitriou M, Dina C, Döring A, Elling U, Ellinghaus D, Elliott P, Engström G, Erdmann J, Esko T, Evans DM, Eyjolfsson GI, Falchi M, Feng W, Ferreira MA, Ferrucci L, Fischer K, Folsom AR, Fortina P, Franke A, Franke L, Frazer IH, Froguel P, Galanello R, Ganesh SK, Garner SF, Gasparini P, Genser B, Gibson QD, Gieger C, Girotto G, Glazer NL, Gögele M, Goodall AH, Greinacher A, Gudbjartsson DF, Hammond C, Harris SE, Hartiala J, Hartikainen AL, Hazen SL, Heckbert SR, Hedblad B, Hengstenberg C, Hersch M, Hicks AA, Holm H, Hottenga JJ, Illig T, Jarvelin MR, Jolley J, Jupe S, Kähönen M, Kamatani N, Kanoni S, Kema IP, Kemp JP, Khadake J, Khaw KT, Kleber ME, Kooner JS, Kovacs P, Kühnel B, Kyrtsonis MC, Labrune Y, Lagou V, Langenberg C, Lehtimäki T, Li X, Liang L, Lloyd-Jones H, Loos RJ, Lopez LM, Lumley T, Lyytikäinen LP, Maerz W, Mägi R, Mangino M, Martin NG, Maschio A, Mateo Leach I, McKnight B, Meacham S, Medland SE, Meisinger C, Melander O, Memari Y, Metspalu A, Miller K, Mitchell BD, Moffatt MF, Montgomery GW, Moore C, Murgia F, Nakamura Y, Nauck M, Navis G, Nolte IM, Nöthlings U, Nutile T, Okada Y, Olafsson I, Onundarson PT, O'Reilly PF, Ouwehand WH, Parracciani D, Parsa A, Paul DS, Penninger JM, Penninx BW, Pirastu M, Pirastu N, Pistis G, Porcu E, Portas L, Porteous D, Pouta A, Pramstaller PP, Prokopenko I, Psaty BM, Pullat J, Radhakrishnan A, Raitakari O, Ramirez-Solis R, Rendon A, Ried JS, Ring SM, Robino A, Rotter JI, Ruggiero D, Ruokonen A, Sala C, Saluments A, Samani NJ, Sambrook J, Sanna S, Schlessinger D, Schmidt CO, Schreiber S, Schunkert H, Scott J, Sehmi J, Serbanovic-Canic J, Shin SY, Shuldiner AR, Sladek R, Smit JH, Smith GD, Smith JG, Smith NL, Snieder H, Soranzo N, Sorice R, Spector TD, Starr JM, Stefansson K, Stemple D, Stephens J, Stumvoll M, Sulem P, Takahashi A, Tan ST, Tanaka T, Tang C, Tang W, Tang WH, Taylor K, Tenesa A, Teumer A, Thein SL, Thorsteinsdottir U, Toniolo D, Tönjes A, Traglia M, Uda M, Ulivi S, van der Harst P, van der Schoot E, van Gilst WH, van Pelt LJ, van Veldhuisen DJ, Verweij N, Visscher PM, Völker U, Vollenweider P, Voss K, Wareham NJ, Wernisch L, Westra HJ, Whitfield JB, Wichmann HE, Wiggins KL, Willemsen G, Winkelmann BR, Wirnsberger G, Wolffenbuttel BH, Yang J, Yang TP, Zhang JH, Zhao JH, Zitting P, Zwaginga JJ.

Author information

1
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom. d.paul@ucl.ac.uk

Abstract

Nearly 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.

PMID:
23570689
PMCID:
PMC3698506
DOI:
10.1101/gr.155127.113
[Indexed for MEDLINE]
Free PMC Article

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