title: Comparison of Methyl-capture Sequencing vs. Infinium 450K methylation array for methylome analysis in clinical samples.
abstract: Interindividual variability in the epigenome has gained tremendous attention for its potential in pathophysiological investigation, disease diagnosis, and evaluation of clinical intervention. DNA methylation is the most studied epigenetic mark in epigenome-wide association studies (EWAS) as it can be detected from limited starting material. Infinium 450K methylation array is the most popular platform for high-throughput profiling of this mark in clinical samples, as it is cost-effective and requires small amounts of DNA. However, this method suffers from low genome coverage and errors introduced by probe cross-hybridization. Whole-genome bisulfite sequencing can overcome these limitations but elevates the costs tremendously. Methyl-Capture Sequencing (MC Seq) is an attractive intermediate solution to increase the methylome coverage in large sample sets. Here we first demonstrate that MC Seq can be employed using DNA amounts comparable to the amounts used for Infinium 450K. Second, to provide guidance when choosing between the 2 platforms for EWAS, we evaluate and compare MC Seq and Infinium 450K in terms of coverage, technical variation, and concordance of methylation calls in clinical samples. Last, since the focus in EWAS is to study interindividual variation, we demonstrate the utility of MC Seq in studying interindividual variation in subjects from different ethnicities.
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.
authors.forename: Ai Ling
authors.initials: AL
authors.lastname: Teh
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.|b School of Computer Engineering, Nanyang Technological University , Singapore.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Lin
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.|c Yong Loo Lin School of Medicine, National University of Singapore , Singapore.
authors.forename: Yubin Ives
authors.initials: YI
authors.lastname: Lim
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.
authors.forename: Chinari Pawan Kumar
authors.initials: CP
authors.lastname: Patro
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.
authors.forename: Clara Yujing
authors.initials: CY
authors.lastname: Cheong
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.
authors.forename: Min
authors.initials: M
authors.lastname: Gong
authors.affiliation: e Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute , Department of Medical Genetics , University of British Columbia , Vancouver , BC , Canada.
authors.forename: Julia L
authors.initials: JL
authors.lastname: MacIsaac
authors.affiliation: b School of Computer Engineering, Nanyang Technological University , Singapore.
authors.forename: Chee-Keong
authors.initials: CK
authors.lastname: Kwoh
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.|d Ludmer Center for Neuroinformatics & Mental Health, Douglas University Mental Health Institute, McGill University , Montreal , Quebec Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Meaney
authors.affiliation: e Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute , Department of Medical Genetics , University of British Columbia , Vancouver , BC , Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.|c Yong Loo Lin School of Medicine, National University of Singapore , Singapore.
authors.forename: Yap-Seng
authors.initials: YS
authors.lastname: Chong
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.|f Centre for Human Evolution, Adaptation and Disease, Liggins Institute, University of Auckland , Auckland , New Zealand.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Holbrook
authors.affiliation: a Singapore Institute for Clinical Sciences, A*STAR , Singapore.|c Yong Loo Lin School of Medicine, National University of Singapore , Singapore.
authors.forename: Neerja
authors.initials: N
authors.lastname: Karnani
mesh_terms: D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005006:Ethnicity / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: DNA methylation; Epigenome-wide association study; Infinium HumanMethylation450 array; Methyl-Capture Sequencing; next generation sequencing