title: Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci.
abstract: The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.2 × 10(-13); FDR<5%). These trans-meQTLs include 1,657 SNP-CpG pairs from different chromosomes and 262 pairs from the same chromosome that are >1 Mb apart. Over 90% of these pairs are replicated (FDR<5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (P<0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states.
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Syed H E
authors.initials: SH
authors.lastname: Zaidi
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, Québec, Canada H3A 0G1.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: 1] INSERM, UMR-S 1166, Paris F-75013, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Paris F-75013, France [3] ICAN Institute for Cardiometabolism and Nutrition, Paris F-75013, France.
authors.forename: Dylan
authors.initials: D
authors.lastname: Aïssi
authors.affiliation: 1] INSERM, UMR-S 1166, Paris F-75013, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Paris F-75013, France [3] ICAN Institute for Cardiometabolism and Nutrition, Paris F-75013, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Germain
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, College Street, Toronto, Ontario, Canada M5T 3M7.
authors.forename: Irfahan
authors.initials: I
authors.lastname: Kassam
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Mike
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Brent W
authors.initials: BW
authors.lastname: Zanke
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, College Street, Toronto, Ontario, Canada M5T 3M7.
authors.forename: France
authors.initials: F
authors.lastname: Gagnon
authors.affiliation: 1] Laboratory of Haematology, La Timone Hospital, Marseille F-13385, France [2] INSERM, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille F-13385, France [3] Aix-Marseille University, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille F-13385, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Morange
authors.affiliation: 1] INSERM, UMR-S 1166, Paris F-75013, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Paris F-75013, France [3] ICAN Institute for Cardiometabolism and Nutrition, Paris F-75013, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.affiliation: Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Wells
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Stephen
authors.identifier: 0000000176850974
authors.initials: S
authors.lastname: Sawcer
authors.affiliation: 1] Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada M5S 1X5 [2] Division of General Surgery, Toronto General Hospital, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, Québec, Canada H3A 0G1.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3 [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5S 1A1 [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A1.
authors.forename: Thomas J
authors.identifier: 0000000213764849
authors.initials: TJ
authors.lastname: Hudson
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005838:Genotype; D006801:Humans; D008214:Lymphocytes; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci