title: Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.
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.
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Casale
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Louella
authors.initials: L
authors.lastname: Vasquez
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.affiliation: Bioinformatics and Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer del Dr. Aiguader, 88, Barcelona 8003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Plaça de la Mercè, 10- 12, Barcelona 8002, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Garrido-Martín
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Watt
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Kousik
authors.initials: K
authors.lastname: Kundu
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro, 3, Madrid 28029, Spain; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Ecker
authors.affiliation: Vertebrate Genomics, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Avik
authors.initials: A
authors.lastname: Datta
authors.affiliation: Vertebrate Genomics, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Richardson
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Burden
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mead
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Mann
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro, 3, Madrid 28029, Spain.
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Fernandez
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Sophia
authors.initials: S
authors.lastname: Rowlston
authors.affiliation: Genome Analysis, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilder
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Farrow
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Shao
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lambourne
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Adriana
authors.initials: A
authors.lastname: Redensek
authors.affiliation: Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, P.O. Box 9101, Nijmegen 6500 HB, the Netherlands; Molecular Developmental Biology, Radboud Institute for Life Sciences, Radboud University, P.O. Box 9101, Nijmegen 6500 HB, the Netherlands.
authors.forename: Cornelis A
authors.initials: CA
authors.lastname: Albers
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63/73, Berlin 14195, Germany.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Amstislavskiy
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Sofie
authors.initials: S
authors.lastname: Ashford
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Berentsen
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bomba
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Bujold
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Caron
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Shu-Huang
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Warren
authors.initials: W
authors.lastname: Cheung
authors.affiliation: Genetic Medicine and Development, University of Geneva Medical School-CMU, 1 Rue Michel-Servet, Geneva 1211, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Delaneau
authors.affiliation: Genetic Medicine and Development, University of Geneva Medical School-CMU, 1 Rue Michel-Servet, Geneva 1211, Switzerland.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Elding
authors.affiliation: Human Genetics Informatics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Irina
authors.initials: I
authors.lastname: Colgiu
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Frederik O
authors.initials: FO
authors.lastname: Bagger
authors.affiliation: Vertebrate Genomics, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Habibi
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iotchkova
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Janssen-Megens
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Bowon
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63/73, Berlin 14195, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Vertebrate Genomics, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Lowy
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Amit
authors.initials: A
authors.lastname: Mandoli
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.affiliation: Institute for Systems Genetics, New York University Langone Medical Center, ACLS West, Room 511, 430 East 29(th) Street, New York, NY 10016, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Maurano
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Morris
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro, 3, Madrid 28029, Spain.
authors.forename: Vera
authors.initials: V
authors.lastname: Pancaldi
authors.affiliation: Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Plesmanlaan 125, Amsterdam 1066CX, the Netherlands.
authors.forename: Farzin
authors.initials: F
authors.lastname: Pourfarzad
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnstrom
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Bioinformatics, Genomics England, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Augusto
authors.initials: A
authors.lastname: Rendon
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63/73, Berlin 14195, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Risch
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Nilofar
authors.initials: N
authors.lastname: Sharifi
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
authors.forename: Marie-Michelle
authors.initials: MM
authors.lastname: Simon
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63/73, Berlin 14195, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Sultan
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro, 3, Madrid 28029, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Walter
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Mattia
authors.initials: M
authors.lastname: Frontini
authors.affiliation: Genetic Medicine and Development, University of Geneva Medical School-CMU, 1 Rue Michel-Servet, Geneva 1211, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: Vertebrate Genomics, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Clarke
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63/73, Berlin 14195, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: Bioinformatics and Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer del Dr. Aiguader, 88, Barcelona 8003, Spain; Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Plaça de la Mercè, 10- 12, Barcelona 8002, Spain; Computational Genomics, Institut Hospital del Mar d'Investigacions Mediques (IMIM), Carrer del Dr. Aiguader, 88, Barcelona 8003, Spain.
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigo
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro, 3, Madrid 28029, Spain; Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Joost H A
authors.initials: JHA
authors.lastname: Martens
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Plesmanlaan 125, Amsterdam 1066CX, the Netherlands; Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Location H7-230, Meibergdreef 9, Amsterdam 1105AZ, the Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK.
authors.forename: Dirk S
authors.initials: DS
authors.lastname: Paul
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stegle
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.affiliation: Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada. Electronic address: tomi.pastinen@mcgill.ca.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK. Electronic address: ns6@sanger.ac.uk.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D057890:Epigenomics; D005260:Female; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D042421:Histone Code; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D040641:Quantitative Trait Loci; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic; D055815:Young Adult
keywords: DNA methylation; EWAS; QTL; allele specific; histone modification; immune; monocyte; neutrophil; t-cell; transription