title: Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits.
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.
authors: Wellcome Trust Sanger Institute, Hinxton, United Kingdom. dp5@sanger.ac.uk
authors: Dirk S
authors: DS
authors: Paul
authors: James P
authors: JP
authors: Nisbet
authors: Tsun-Po
authors: TP
authors: Yang
authors: Stuart
authors: S
authors: Meacham
authors: Augusto
authors: A
authors: Rendon
authors: Katta
authors: K
authors: Hautaviita
authors: Jonna
authors: J
authors: Tallila
authors: Jacqui
authors: J
authors: White
authors: Marloes R
authors: MR
authors: Tijssen
authors: Suthesh
authors: S
authors: Sivapalaratnam
authors: Hanneke
authors: H
authors: Basart
authors: Mieke D
authors: MD
authors: Trip
authors: Berthold
authors: B
authors: Göttgens
authors: Nicole
authors: N
authors: Soranzo
authors: Willem H
authors: WH
authors: Ouwehand
authors: Panos
authors: P
authors: Deloukas
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002843:Chromatin / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004900:Erythroblasts / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D008264:Macrophages / Q000378:metabolism; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D010641:Phenotype; D011519:Proto-Oncogenes; D040641:Quantitative Trait Loci; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human