title: Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation.
abstract: BACKGROUND
  CpG methylation variation is involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions through the application of targeted arrays. We generate whole-genome bisulfite sequencing data for approximately 30 adipose and blood samples from monozygotic and dizygotic twins for the characterization of non-genetic and genetic effects at single-site resolution.
  
  
  RESULTS
  Purely invariable CpGs display a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs account for approximately 15-20 % of total CpGs per tissue, are enriched in enhancer-associated regions and depleted in promoters, and single nucleotide polymorphisms at CpGs are a frequent confounder of extreme methylation variation. Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific. Tobacco smoking is associated with differential methylation in blood with no evidence of this exposure impacting cell counts. Opposite to non-genetic effects, genetic effects of CpG methylation are shared across tissues and thus limit inter-tissue epigenetic drift. CpH methylation is rare, and shows similar characteristics of variation patterns as CpGs.
  
  
  CONCLUSIONS
  Our study highlights the utility of low pass whole-genome bisulfite sequencing in identifying methylome variation beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues requires assessment of understudied intergenic CpGs distal to gene promoters to reveal the full extent of inter-individual variation.
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. stephan.busche@mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. stephan.busche@mcgill.ca.
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. shao.xiaojian@mail.mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. shao.xiaojian@mail.mcgill.ca.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Shao
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. max.caron@mail.mcgill.ca.
authors.forename: Maxime
authors.initials: M
authors.lastname: Caron
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. tony.kwan@mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. tony.kwan@mcgill.ca.
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. fiona.allum@mail.mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. fiona.allum@mail.mcgill.ca.
authors.forename: Fiona
authors.initials: F
authors.lastname: Allum
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. warren.cheung@mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. warren.cheung@mcgill.ca.
authors.forename: Warren A
authors.initials: WA
authors.lastname: Cheung
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. bing.ge@mail.mcgill.ca.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. susan.westfall@mail.mcgill.ca.
authors.forename: Susan
authors.initials: S
authors.lastname: Westfall
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. marie-michelle.simon@mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. marie-michelle.simon@mcgill.ca.
authors.forename: Marie-Michelle
authors.initials: MM
authors.lastname: Simon
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, UK. amy.barrett@ocdem.ox.ac.uk.
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. jordana.bell@kcl.ac.uk.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.|Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: William Harvey Research Institute, Queen Mary University of London, London, UK. p.deloukas@qmul.ac.uk.|Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. p.deloukas@qmul.ac.uk.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: School of Computer Science, McGill University, Montreal, Quebec, Canada. blanchem@cs.mcgill.ca.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blanchette
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. guil.bourque@mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. guil.bourque@mcgill.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. tim.spector@kcl.ac.uk.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. mark.lathrop3@gmail.com.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. mark.lathrop3@gmail.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada. tomi.pastinen@mcgill.ca.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. tomi.pastinen@mcgill.ca.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, 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: D000273:Adipose Tissue / Q000378:metabolism; D001769:Blood / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D012907:Smoking / Q000235:genetics; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic