DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition.
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ABSTRACT:
SUBMITTER: Peter CJ
PROVIDER: S-EPMC5036982 | biostudies-literature | 2016 Nov
REPOSITORIES: biostudies-literature
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DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition.
Peter Cyril J CJ Fischer Laura K LK Kundakovic Marija M Garg Paras P Jakovcevski Mira M Dincer Aslihan A Amaral Ana C AC Ginns Edward I EI Galdzicka Marzena M Bryce Cyralene P CP Ratner Chana C Waber Deborah P DP Mokler David D Medford Gayle G Champagne Frances A FA Rosene Douglas L DL McGaughy Jill A JA Sharp Andrew J AJ Galler Janina R JR Akbarian Schahram S
Biological psychiatry 20160326 10
<h4>Background</h4>Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored.<h4>Methods</h4>We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the ...[more]
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Project description:BackgroundFew studies have examined prognostic outcomes-associated molecular signatures other than overall survival (OS) for gastric cancer (GC). We aimed to identify DNA methylation biomarkers associated with multiple prognostic outcomes of GC in an epigenome-wide association study.MethodsBased on the Cancer Genome Atlas (TCGA), DNA methylation loci associated with OS (n = 381), disease-specific survival (DSS, n = 372), and progression-free interval (PFI, n = 383) were discovered in training set subjects (false discovery rates < 0.05) randomly selected for each prognostic outcome and were then validated in remaining subjects (P-values < 0.05). Key CpGs simultaneously validated for OS, DSS, and PFI were further assessed for disease-free interval (DFI, n = 247). Gene set enrichment analyses were conducted to explore the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways simultaneously enriched for multiple GC prognostic outcomes. Methylation correlated blocks (MCBs) were identified for co-methylation patterns associated with GC prognosis. Based on key CpGs, risk score models were established to predict four prognostic outcomes. Spearman correlation analyses were performed between key CpG sites and their host gene mRNA expression.ResultsWe newly identified DNA methylation of seven CpGs significantly associated with OS, DSS, and PFI of GC, including cg10399824 (GRK5), cg05275153 (RGS12), cg24406668 (MMP9), cg14719951(DSC3), and cg25117092 (MED12L), and two in intergenic regions (cg11348188 and cg11671115). Except cg10399824 and cg24406668, five of them were also significantly associated with DFI of GC. Neuroactive ligand-receptor interaction pathway was suggested to play a key role in the effect of DNA methylation on GC prognosis. Consistent with individual CpG-level association, three MCBs involving cg11671115, cg14719951, and cg24406668 were significantly associated with multiple prognostic outcomes of GC. Integrating key CpG loci, two risk score models performed well in predicting GC prognosis. Gene body DNA methylation of cg14719951, cg10399824, and cg25117092 was associated with their host gene expression, whereas no significant associations between their host gene expression and four clinical prognostic outcomes of GC were observed.ConclusionsWe newly identified seven CpGs associated with OS, DSS, and PFI of GC, with five of them also associated with DFI, which might inform patient stratification in clinical practices.
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