Paul, DS;
Nisbet, JP;
Yang, TP;
Meacham, S;
Rendon, A;
Hautaviita, K;
Tallila, J;
... Deloukas, P; + view all
(2011)
Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits.
PLoS Genet
, 7
(6)
, Article e1002139. 10.1371/journal.pgen.1002139.
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Abstract
Turning genetic discoveries identified in genome-wide association (GWA) studies into biological mechanisms is an important challenge in human genetics. Many GWA signals map outside exons, suggesting that the associated variants may lie within regulatory regions. We applied the formaldehyde-assisted isolation of regulatory elements (FAIRE) method in a megakaryocytic and an erythroblastoid cell line to map active regulatory elements at known loci associated with hematological quantitative traits, coronary artery disease, and myocardial infarction. We showed that the two cell types exhibit distinct patterns of open chromatin and that cell-specific open chromatin can guide the finding of functional variants. We identified an open chromatin region at chromosome 7q22.3 in megakaryocytes but not erythroblasts, which harbors the common non-coding sequence variant rs342293 known to be associated with platelet volume and function. Resequencing of this open chromatin region in 643 individuals provided strong evidence that rs342293 is the only putative causative variant in this region. We demonstrated that the C- and G-alleles differentially bind the transcription factor EVI1 affecting PIK3CG gene expression in platelets and macrophages. A protein-protein interaction network including up- and down-regulated genes in Pik3cg knockout mice indicated that PIK3CG is associated with gene pathways with an established role in platelet membrane biogenesis and thrombus formation. Thus, rs342293 is the functional common variant at this locus; to the best of our knowledge this is the first such variant to be elucidated among the known platelet quantitative trait loci (QTLs). Our data suggested a molecular mechanism by which a non-coding GWA index SNP modulates platelet phenotype.
| Type: | Article |
|---|---|
| Title: | Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1002139 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1002139 |
| Language: | English |
| Additional information: | © 2011 Paul et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Wellcome Trust (091746/Z/10/Z). DSP is a Marie Curie Training Fellow and supported by NetSim (215820). SM is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. AR is funded by the British Heart Foundation Program Grant RG/09/12/28096. MRT is funded by a Marie Curie Intra-European Fellowship (237296), and BG by Leukaemia and Lymphoma Research and the NIHR Cambridge Biomedical Research Centre. WHO is supported by a NIHR Program Grant to NHSBT (RP-PG-0310-1002). The Cardiogenics and MuTHER consortia are funded under grants from the European Commission through the FP6 (LSHM-CT-2006-037593) and the Wellcome Trust (081917/Z/07/Z), respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | Animals, Blood Platelets, Chromatin, Chromosomes, Human, Pair 7, Class Ib Phosphatidylinositol 3-Kinase, DNA-Binding Proteins, Erythroblasts, Female, Gene Expression Profiling, Genome-Wide Association Study, Humans, Macrophages, Megakaryocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Genetic, Phenotype, Proto-Oncogenes, Quantitative Trait Loci, Signal Transduction, Transcription Factors |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1380204 |
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