title: Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood.
abstract: Childhood obesity is a major public health issue. Here we investigated whether differential DNA methylation was associated with childhood obesity. We studied DNA methylation profiles in whole blood from 78 obese children (mean BMI Z-score: 2.6) and 71 age- and sex-matched controls (mean BMI Z-score: 0.1). DNA samples from obese and control groups were pooled and analyzed using the Infinium HumanMethylation450 BeadChip array. Comparison of the methylation profiles between obese and control subjects revealed 129 differentially methylated CpG (DMCpG) loci associated with 80 unique genes that had a greater than 10% difference in methylation (P-value < 0.05). The top pathways enriched among the DMCpGs included developmental processes, immune system regulation, regulation of cell signaling, and small GTPase-mediated signal transduction. The associations between the methylation of selected DMCpGs with childhood obesity were validated using sodium bisulfite pyrosequencing across loci within the FYN, PIWIL4, and TAOK3 genes in individual subjects. Three CpG loci within FYN were hypermethylated in obese individuals (all P < 0.01), while obesity was associated with lower methylation of CpG loci within PIWIL4 (P = 0.003) and TAOK3 (P = 0.001). After building logistic regression models, we determined that a 1% increase in methylation in TAOK3, multiplicatively decreased the odds of being obese by 0.91 (95% CI: 0.86 - 0.97), and an increase of 1% methylation in FYN CpG3, multiplicatively increased the odds of being obese by 1.03 (95% CI: 0.99 - 1.07). In conclusion, these findings provide evidence that childhood obesity is associated with specific DNA methylation changes in whole blood, which may have utility as biomarkers of obesity risk.
authors.affiliation: a Telethon Institute for Child Health Research; University of Western Australia ; Perth, Australia.
authors.forename: R C
authors.initials: RC
authors.lastname: Huang
authors.affiliation: b Academic Unit of Human Development and Health; Faculty of Medicine; University of Southampton ; Southampton , UK.
authors.forename: E S
authors.initials: ES
authors.lastname: Garratt
authors.affiliation: c Singapore Institute for Clinical Sciences (SICS); A*STAR; Brenner Center for Molecular Medicine ; Singapore.|d School of Computer Engineering; Nanyang Technological University (NTU) ; Singapore.
authors.forename: H
authors.initials: H
authors.lastname: Pan
authors.affiliation: c Singapore Institute for Clinical Sciences (SICS); A*STAR; Brenner Center for Molecular Medicine ; Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: a Telethon Institute for Child Health Research; University of Western Australia ; Perth, Australia.
authors.forename: E A
authors.initials: EA
authors.lastname: Davis
authors.affiliation: e MRC Lifecourse Epidemiology Unit; University of Southampton ; Southampton , UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Barton
authors.affiliation: b Academic Unit of Human Development and Health; Faculty of Medicine; University of Southampton ; Southampton , UK.
authors.forename: G C
authors.initials: GC
authors.lastname: Burdge
authors.affiliation: e MRC Lifecourse Epidemiology Unit; University of Southampton ; Southampton , UK.|f NIHR Southampton Biomedical Research Center; University of Southampton and University Hospital Southampton NHS Foundation Trust; Southampton, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: Godfrey
authors.affiliation: c Singapore Institute for Clinical Sciences (SICS); A*STAR; Brenner Center for Molecular Medicine ; Singapore.|g Yong Loo Lin School of Medicine; National University of Singapore (NUS) ; Singapore.
authors.forename: J D
authors.initials: JD
authors.lastname: Holbrook
authors.affiliation: b Academic Unit of Human Development and Health; Faculty of Medicine; University of Southampton ; Southampton , UK.|h Faculty of Natural and Environmental Sciences; University of Southampton ; Southampton , UK.
authors.forename: K A
authors.initials: KA
authors.lastname: Lillycrop
mesh_terms: D000293:Adolescent; D060565:Argonaute Proteins / Q000235:genetics*; D002648:Child; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D016015:Logistic Models; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D063766:Pediatric Obesity / Q000097:blood / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics*; D016601:RNA-Binding Proteins; D017422:Sequence Analysis, DNA / Q000379:methods; D000099317:Hippo Kinases
chemical_list: D060565:Argonaute Proteins; D017346:Protein Serine-Threonine Kinases; D051076:Proto-Oncogene Proteins c-fyn; D016601:RNA-Binding Proteins; C556795:PIWIL4 protein, human; C109163:STK24 protein, human; D000099317:Hippo Kinases; C494957:FYN protein, human
keywords: biomarkers; childhood obesity; epigenetics; genome-wide; methylation