Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

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• dc.contributor.author Chen, Luca
• dc.contributor.author Garrido Martín, Diego, 1992-ca
• dc.contributor.author Guigó Serra, Rodericca
• dc.contributor.author Soranzo, Nicoleca
• dc.date.accessioned 2017-03-31T10:44:38Z
• dc.date.available 2017-03-31T10:44:38Z
• dc.date.issued 2016
• dc.description.abstract Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.
• dc.description.sponsorship This work was predominantly funded by the EU FP7 High Impact Project BLUEPRINT (HEALTH-F5-2011-282510) and the Canadian Institutes of Health Research (CIHR EP1-120608). We thank Simon Dökel, Matthias Linser, Alexander Kovacsovics, and Daniela Balzereit for excellent technical skills on the Illumina platform and Mark Kristiansen (UCL Genomics) for processing the Illumina Infinium HumanMethylation450 BeadChIPs. We gratefully acknowledge the participation of all NIHR Cambridge BioResource volunteers. We thank the Cambridge BioResource staff for their help with volunteer recruitment. We thank members of the Cambridge BioResource SAB and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. The research leading to these results has also received funding from the European Molecular Biology Laboratory, the Max Planck Society, the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208 and Spanish National Bioinformatics Institute (INB-ISCIII) PT13/0001/0021 co-funded by FEDER “Una Manera de hacer Europa.” D.G.-M. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship, M.F. was supported by the BHF Cambridge Centre of Excellence (RE/13/6/30180), K.D. is funded as an HSST trainee by NHS Health Education England, S.E. is supported by a fellowship from “La Caixa”, V.P. is supported by an FEBS long-term fellowship, and N.S.’s research is supported by the Wellcome Trust (WT098051 and WT091310), the EU FP7 (EPIGENESYS257082), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre. The Blood and Transplant Unit (BTRU) in Donor Health and Genomics is part of, and funded by, the National Institute for Health Research (NIHR) and is a partnership between the University of Cambridge and NHS Blood and Transplant (NHSBT) in collaboration with the University of Oxford and the Wellcome Trust Sanger Institute. The T cell data were produced by the McGill Epigenomics Mapping Centre (EMC McGill). It is funded under the Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) by the Canadian Institutes of Health Research and by Genome Quebec (CIHR EP1-120608), with additional support from Genome Canada and FRSQ. T.P. holds a Canada Research Chair. P.F. is a member of the Scientific Advisory Board of Omicia, Inc. S.W. is now an employee of GENOMICS plc, with some minor share options, although all work was conducted when he was an employee of EMBL-EBI.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Chen L, Ge B, Paolo Casale F, Vasquez L, Kwan T, Garrido-Martín D et al. Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells. Cell. 2016;167(5):1398-414. DOI: 10.1016/j.cell.2016.10.026
• dc.identifier.doi http://dx.doi.org/10.1016/j.cell.2016.10.026
• dc.identifier.issn 0092-8674
• dc.identifier.uri http://hdl.handle.net/10230/28353
• dc.language.iso eng
• dc.publisher Elsevierca
• dc.relation.ispartof Cell. 2016;167(5):1398-414
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/282510
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/257082
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SEV2012-0208
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.cell.2016.10.026. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Immune
• dc.subject.keyword Monocyte
• dc.subject.keyword Neutrophil
• dc.subject.keyword T-cell
• dc.subject.keyword EWAS
• dc.subject.keyword Histone modification
• dc.subject.keyword DNA methylation
• dc.subject.keyword Transription
• dc.subject.keyword Allele specific
• dc.subject.keyword QTL
• dc.title Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cellsca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion