title: Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants.
abstract: Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Fiona
authors.initials: F
authors.lastname: Allum
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Shao
authors.affiliation: Institute of Nutrition and Functional Foods (INAF), Université Laval, 2440 Hochelaga Boulevard, Québec, Québec, Canada G1V 0A6.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Guénard
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Marie-Michelle
authors.initials: MM
authors.lastname: Simon
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Maxime
authors.initials: M
authors.lastname: Caron
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: John
authors.initials: J
authors.lastname: Lambourne
authors.affiliation: Québec Heart and Lung Institute, Université Laval, 2725 Sainte-Foy Road, Québec, Québec, Canada G1V 4G5.
authors.forename: Julie
authors.initials: J
authors.lastname: Lessard
authors.affiliation: Department of Medical Sciences, Uppsala University, Akademiska sjukhuset Ingång 40, Uppsala 75185, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Tandre
authors.affiliation: 1] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Dag Hammarskjölds väg 14B, Uppsala 75185, Sweden [2] Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 14B, Uppsala 75185, Sweden.
authors.forename: Åsa K
authors.identifier: 000000015413204X
authors.initials: ÅK
authors.lastname: Hedman
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: Department of Medical Sciences, Uppsala University, Akademiska sjukhuset Ingång 40, Uppsala 75185, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.affiliation: 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7JU, UK [3] Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Headington, Oxford OX3 7JU, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Panos
authors.identifier: 000000019251070X
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Roche NimbleGen, 500 South Rosa Road, Madison, Wisconsin 53719, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Richmond
authors.affiliation: Roche NimbleGen, 500 South Rosa Road, Madison, Wisconsin 53719, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Burgess
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, Lambeth Palace Road, London SE17EH, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Québec Heart and Lung Institute, Université Laval, 2725 Sainte-Foy Road, Québec, Québec, Canada G1V 4G5.
authors.forename: André
authors.initials: A
authors.lastname: Tchernof
authors.affiliation: Québec Heart and Lung Institute, Université Laval, 2725 Sainte-Foy Road, Québec, Québec, Canada G1V 4G5.
authors.forename: Simon
authors.initials: S
authors.lastname: Marceau
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Institute of Nutrition and Functional Foods (INAF), Université Laval, 2440 Hochelaga Boulevard, Québec, Québec, Canada G1V 0A6.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Vohl
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: 1] Department of Human Genetics, McGill University, 740 Docteur-Penfield Avenue, Montreal, Québec , Canada H3A 0G1 [2] McGill University and Genome Quebec Innovation Centre, 740 Docteur-Penfield Avenue, Montreal, Québec, Canada H3A 0G1.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D014280:Triglycerides / Q000097:blood* / Q000235:genetics
chemical_list: D018955:CD36 Antigens; D008076:Cholesterol, HDL; D014280:Triglycerides