title: Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.
abstract: The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples.
  
  
  
  We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases.
  
  
  
  Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Warren A
authors.initials: WA
authors.lastname: Cheung
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Shao
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Andréanne
authors.initials: A
authors.lastname: Morin
authors.affiliation: Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Inserm U1209, CNRS, University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Siroux
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Inserm U1209, CNRS, University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Dylan
authors.initials: D
authors.lastname: Aïssi
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: 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: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Fiona
authors.initials: F
authors.lastname: Allum
authors.affiliation: Institute of Nutrition and Functional Foods (INAF), Laval University, Québec, QC, G1V 0A6, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Guénard
authors.affiliation: Genetic Variation and Human Diseases Unit, UMR-946, INSERM, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bouzigon
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Marie-Michelle
authors.initials: MM
authors.lastname: Simon
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Elodie
authors.initials: E
authors.lastname: Boulier
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Adriana
authors.initials: A
authors.lastname: Redensek
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: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
authors.forename: Avik
authors.initials: A
authors.lastname: Datta
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Clarke
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
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: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.|Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK.
authors.forename: Dirk S
authors.initials: DS
authors.lastname: Paul
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: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Québec Heart and Lung Institute, Laval University, Québec, QC, G1V 4G5, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Tchernof
authors.affiliation: Institute of Nutrition and Functional Foods (INAF), Laval University, Québec, QC, G1V 0A6, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Vohl
authors.affiliation: Genetic Variation and Human Diseases Unit, UMR-946, INSERM, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.affiliation: Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Inserm U1209, CNRS, University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.|Pédiatrie, Centre Hospitalier Universitaire (CHU) Grenoble Alpes, Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pin
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: Faculty of Science, Department of Molecular Biology, Radboud University, Nijmegen, 6525GA, The Netherlands.
authors.forename: Hendrick G
authors.initials: HG
authors.lastname: Stunnenberg
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, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada. tomi.pastinen@gmail.com.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. tomi.pastinen@gmail.com.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada. elin.grundberg@mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. elin.grundberg@mcgill.ca.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
mesh_terms: D000483:Alleles; D055012:Chromosomal Position Effects; D018899:CpG Islands; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci