Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

Lu Chen; Bing Ge; Francesco Paolo Casale; Louella Vasquez; Tony Kwan; Diego Garrido-Martín; Stephen Watt; Ying Yan; Kousik Kundu; Simone Ecker; Avik Datta; David Richardson; Frances Burden; Daniel Mead; Alice L Mann; Jose Maria Fernandez; Sophia Rowlston; Steven P Wilder; Samantha Farrow; Xiaojian Shao; John J Lambourne; Adriana Redensek; Cornelis A Albers; Vyacheslav Amstislavskiy; Sofie Ashford; Kim Berentsen; Lorenzo Bomba; Guillaume Bourque; David Bujold; Stephan Busche; Maxime Caron; Shu-Huang Chen; Warren Cheung; Oliver Delaneau; Emmanouil T Dermitzakis; Heather Elding; Irina Colgiu; Frederik O Bagger; Paul Flicek; Ehsan Habibi; Valentina Iotchkova; Eva Janssen-Megens; Bowon Kim; Hans Lehrach; Ernesto Lowy; Amit Mandoli; Filomena Matarese; Matthew T Maurano; John A Morris; Vera Pancaldi; Farzin Pourfarzad; Karola Rehnstrom; Augusto Rendon; Thomas Risch; Nilofar Sharifi; Marie-Michelle Simon; Marc Sultan; Alfonso Valencia; Klaudia Walter; Shuang-Yin Wang; Mattia Frontini; Stylianos E Antonarakis; Laura Clarke; Marie-Laure Yaspo; Stephan Beck; Roderic Guigo; Daniel Rico; Joost H A Martens; Willem H Ouwehand; Taco W Kuijpers; Dirk S Paul; Hendrik G Stunnenberg; Oliver Stegle; Kate Downes; Tomi Pastinen; Nicole Soranzo

doi:10.1016/j.cell.2016.10.026

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

Cell. 2016 Nov 17;167(5):1398-1414.e24. doi: 10.1016/j.cell.2016.10.026.

Authors

Lu Chen¹, Bing Ge², Francesco Paolo Casale³, Louella Vasquez⁴, Tony Kwan², Diego Garrido-Martín⁵, Stephen Watt⁴, Ying Yan⁴, Kousik Kundu¹, Simone Ecker⁶, Avik Datta⁷, David Richardson⁷, Frances Burden⁸, Daniel Mead⁴, Alice L Mann⁴, Jose Maria Fernandez⁹, Sophia Rowlston⁸, Steven P Wilder¹⁰, Samantha Farrow⁸, Xiaojian Shao², John J Lambourne¹¹, Adriana Redensek², Cornelis A Albers¹², Vyacheslav Amstislavskiy¹³, Sofie Ashford⁸, Kim Berentsen¹⁴, Lorenzo Bomba⁴, Guillaume Bourque², David Bujold², Stephan Busche², Maxime Caron², Shu-Huang Chen², Warren Cheung², Oliver Delaneau¹⁵, Emmanouil T Dermitzakis¹⁵, Heather Elding⁴, Irina Colgiu¹⁶, Frederik O Bagger¹⁷, Paul Flicek⁷, Ehsan Habibi¹⁴, Valentina Iotchkova¹⁸, Eva Janssen-Megens¹⁴, Bowon Kim¹⁴, Hans Lehrach¹³, Ernesto Lowy⁷, Amit Mandoli¹⁴, Filomena Matarese¹⁴, Matthew T Maurano¹⁹, John A Morris², Vera Pancaldi⁹, Farzin Pourfarzad²⁰, Karola Rehnstrom⁸, Augusto Rendon²¹, Thomas Risch¹³, Nilofar Sharifi¹⁴, Marie-Michelle Simon², Marc Sultan¹³, Alfonso Valencia⁹, Klaudia Walter⁴, Shuang-Yin Wang¹⁴, Mattia Frontini²², Stylianos E Antonarakis¹⁵, Laura Clarke⁷, Marie-Laure Yaspo¹³, Stephan Beck²³, Roderic Guigo²⁴, Daniel Rico²⁵, Joost H A Martens¹⁴, Willem H Ouwehand²⁶, Taco W Kuijpers²⁷, Dirk S Paul²⁸, Hendrik G Stunnenberg¹⁴, Oliver Stegle³, Kate Downes⁸, Tomi Pastinen²⁹, Nicole Soranzo³⁰

Affiliations

¹ 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.
² Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada.
³ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
⁴ Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
⁵ 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.
⁶ 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.
⁷ Vertebrate Genomics, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
⁸ 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.
⁹ Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro, 3, Madrid 28029, Spain.
¹⁰ Genome Analysis, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
¹¹ 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.
¹² 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.
¹³ Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63/73, Berlin 14195, Germany.
¹⁴ Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525GA, the Netherlands.
¹⁵ Genetic Medicine and Development, University of Geneva Medical School-CMU, 1 Rue Michel-Servet, Geneva 1211, Switzerland.
¹⁶ Human Genetics Informatics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
¹⁷ 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.
¹⁸ 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.
¹⁹ Institute for Systems Genetics, New York University Langone Medical Center, ACLS West, Room 511, 430 East 29(th) Street, New York, NY 10016, USA.
²⁰ Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Plesmanlaan 125, Amsterdam 1066CX, the Netherlands.
²¹ Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Bioinformatics, Genomics England, Charterhouse Square, London EC1M 6BQ, UK.
²² 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.
²³ UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
²⁴ 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.
²⁵ 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.
²⁶ 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.
²⁷ 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.
²⁸ 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.
²⁹ Human Genetics, McGill University, 740 Dr. Penfield, Montreal, QC H3A 0G1, Canada. Electronic address: [email protected].
³⁰ 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: [email protected].

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.

Keywords: DNA methylation; EWAS; QTL; allele specific; histone modification; immune; monocyte; neutrophil; t-cell; transription.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Alternative Splicing
Epigenomics*
Female
Genetic Predisposition to Disease
Hematopoietic Stem Cells / metabolism
Histone Code
Humans
Immune System Diseases / genetics*
Male
Middle Aged
Monocytes / metabolism*
Neutrophils / metabolism*
Quantitative Trait Loci
T-Lymphocytes / metabolism*
Transcription, Genetic*
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding