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Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age.

ABSTRACT: The aim of this study was to identify placental DNA methylation (DNAm) variations associated with adiposity at 3 years of age. We quantified placental DNAm using the Infinium MethylationEPIC BeadChips. We assessed associations between DNAm at single-CpGs and skinfold thickness using robust linear regression models adjusted for gestational age, child's sex, age at follow-up and cellular heterogeneity. We sought replication of DNAm association with child adiposity in an independent cohort. We quantified placental mRNA levels for annotated gene using qRT-PCR and tested for correlation with DNAm. Lower DNAm at cg22593959 and cg22436429 was associated with higher adiposity (? = -1.18, q = 0.002 and ? = -0.82, q = 0.04). The cg22593959 is located in an intergenic region (chr7q31.3), whereas cg22436429 is within the TFAP2E gene (1p34.3). DNAm at cg22593959 and cg22436429 was correlated with mRNA levels at FAM3C (rs = -0.279, p = 0.005) and TFAP2E (rs = 0.216, p = 0.03). In an independent cohort, the association between placental DNAm at cg22593959 and childhood adiposity was of similar strength and direction (? = -3.8 ± 4.1, p = 0.36), yet non-significant. Four genomic regions were also associated with skinfold thickness within FMN1, MAGI2, SKAP2 and BMPR1B genes. We identified placental epigenetic variations associated with adiposity at 3 years of age suggesting that childhood fat accretion patterns might be established during fetal life.

SUBMITTER: Gagne-Ouellet V

PROVIDER: S-EPMC7582906 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age.

Gagné-Ouellet Valérie V Breton Edith E Thibeault Kathrine K Fortin Carol-Ann CA Desgagné Véronique V Girard Tremblay Élise É Cardenas Andres A Guérin Renée R Perron Patrice P Hivert Marie-France MF Bouchard Luigi L

International journal of molecular sciences 20200929 19

The aim of this study was to identify placental DNA methylation (DNAm) variations associated with adiposity at 3 years of age. We quantified placental DNAm using the Infinium MethylationEPIC BeadChips. We assessed associations between DNAm at single-CpGs and skinfold thickness using robust linear regression models adjusted for gestational age, child's sex, age at follow-up and cellular heterogeneity. We sought replication of DNAm association with child adiposity in an independent cohort. We quan ...[more]

PMID: 33003475

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Project description:Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva-Boston, and the Generation R Study-Rotterdam). We performed covariate-adjusted epigenome-wide association meta-analysis and employed pathway and regional analyses of results. Seven-hundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylation - time interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization.

Project description:BackgroundIncreased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.MethodsGenome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.ResultsFor EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.ConclusionsWe identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.

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Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age.

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Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age.

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