Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight

Abstract Background High early postnatal weight gain has been associated with childhood adiposity; however, the mechanism remains unknown. DNA methylation is a hypothesised mechanism linking early life exposures and subsequent disease. However, epigenetic changes associated with high early weight gain have not previously been investigated. Our aim was to investigate the associations between early weight gain, peripheral blood DNA methylation, and subsequent overweight/obese. Data from the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort were used to estimate associations between early postnatal weight gain and epigenome-wide DNA CpG site methylation (Illumina 450 K Methylation Beadchip) in blood in childhood (n = 125) and late adolescence (n = 96). High weight gain in the first year (a change in weight z‐scores > 0.67), both unconditional (rapid weight gain) and conditional on birthweight (rapid thrive), was related to individual CpG site methylation and across regions using the meffil pipeline, with and without adjustment for cell type proportions, and with 5% false discovery rate correction. Variation in methylation at high weight gain-associated CpG sites was then examined with regard to body composition measures in childhood and adolescence. Replication of the differentially methylated CpG sites was sought using whole-blood DNA samples from 104 children from the UK Southampton Women’s Survey. Results Rapid infant weight gain was associated with small (+ 1% change) increases in childhood methylation (age 7) for two distinct CpG sites (cg01379158 (NT5M) and cg11531579 (CHFR)). Childhood methylation at one of these CpGs (cg11531579) was also higher in those who experienced rapid weight gain and were subsequently overweight/obese in adolescence (age 17). Rapid weight gain was not associated with differential DNA methylation in adolescence. Childhood methylation at the cg11531579 site was also suggestively associated with rapid weight gain in the replication cohort. Conclusions This study identified associations between rapid weight gain in infancy and small increases in childhood methylation at two CpG sites, one of which was replicated and was also associated with subsequent overweight/obese. It will be important to determine whether loci are markers of early rapid weight gain across different, larger populations. The mechanistic relevance of these differentially methylated sites requires further investigation.

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The Study of Breast Milk IGF-1, Leptin, Ghrelin and Adiponectin Levels as Possible Reasons of High Weight Gain in Breast-Fed Infants

Annals of Nutrition and Metabolism ◽

10.1159/000367998 ◽

2014 ◽

Vol 65 (4) ◽

pp. 317-323 ◽

Cited By ~ 29

Author(s):

Igor Ya Kon ◽

Natalia M. Shilina ◽

Maria V. Gmoshinskaya ◽

Tatiana A. Ivanushkina

Keyword(s):

Weight Gain ◽

Breast Milk ◽

High Weight ◽

High Weight Gain ◽

Breast Fed

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Infancy Weight Gain Predicts Childhood Body Fat and Age at Menarche in Girls

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-2489 ◽

2009 ◽

Vol 94 (5) ◽

pp. 1527-1532 ◽

Cited By ~ 157

Author(s):

Ken K. Ong ◽

Pauline Emmett ◽

Kate Northstone ◽

Jean Golding ◽

Imogen Rogers ◽

...

Keyword(s):

Weight Gain ◽

Body Fat ◽

Odds Ratio ◽

Dual Energy ◽

Birth Cohort Study ◽

Age At Menarche ◽

Rapid Weight Gain ◽

X Ray ◽

Childhood Adiposity ◽

Postnatal Weight Gain

Abstract Context: Rapid postnatal weight gain has been associated with subsequent increased childhood adiposity. However, the contribution of rapid weight gain during specific infancy periods is not clear. Objective: We aimed to determine which periods of infancy weight gain are related to childhood adiposity and also to age at menarche in UK girls. Design, Setting, and Participants: A total of 2715 girls from a prospective UK birth cohort study participated in the study. Main Outcome Measures: Routinely measured weights and lengths at ages 2, 9, and 19 months were extracted from the local child health computer database. Body composition was assessed by dual-energy x-ray absorptiometry at age 10 yr, and age at menarche was assessed by questionnaire (categorized into three groups: <12.0, 12.0–13.0, and >13.0 yr). Results: Faster early infancy weight gain between 0 and 2 months and also 2 to 9 months were associated with increased body fat mass relative to lean mass at age 10 yr and also with earlier age at menarche. Each +1 unit gain in weight sd score between 0 and 9 months was associated with an odds ratio (95% confidence interval) = 1.48 (1.27–1.60) for overweight (body mass index > 85th centile) at 10 yr, and 1.34 (1.21–1.49) for menarche at less than 12 yr. In contrast, subsequent weight gain between 9 and 19 months was not associated with later adiposity or age at menarche. Conclusions: In developed settings, rapid weight gain during the first 9 months of life is a risk factor for both increased childhood adiposity and early menarche in girls.

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Coat colour in mouse populations selected for weight gain: support for hitchhiking, not pleiotropy

Genetics Research ◽

10.1017/s0016672312000778 ◽

2013 ◽

Vol 95 (1) ◽

pp. 4-13 ◽

Cited By ~ 1

Author(s):

PHILIP W. HEDRICK

Keyword(s):

Weight Gain ◽

Allele Frequency ◽

High Weight ◽

Coat Colour ◽

Correlated Response ◽

Term Selection ◽

Low Weight ◽

High Weight Gain ◽

Frequency Changes ◽

Positive Correlations

SummaryWith many molecular markers in many species, research efforts in quantitative genetics have focused on dissecting these traits and understanding the importance of factors such as correlated response due to hitchhiking or pleiotropy. Here, in an examination of long-term selection experiments in mice, the evidence strongly supports the primary importance of hitchhiking on the coat colour loci brown and dilute in mice selected for high weight gain. First, the amount of observed change in coat colour allele frequency could not be explained by genetic drift alone, implying that selection was of high importance. Second, the allele frequency changes included reversals in the direction change, but there were still positive correlations in the early generations with differences in weight gain between the phenotypes. Third, the correlation between the change in allele frequencies and phenotypic difference in weight gain declined over time, consistent with the decay expected from linkage associations. Fourth, the changes at both loci in a short-term selection experiment for low weight gain were in the opposite direction than the changes in the contemporaneous related population selected for high weight gain.

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Intensity-Specific Differential Leukocyte DNA Methylation in Physical (In)Activity: An Exploratory Approach

Twin Research and Human Genetics ◽

10.1017/thg.2018.10 ◽

2018 ◽

Vol 21 (2) ◽

pp. 101-111 ◽

Cited By ~ 3

Author(s):

Maarten Caspers ◽

Sara Blocquiaux ◽

Ruben Charlier ◽

Sara Knaeps ◽

Johan Lefevre ◽

...

Keyword(s):

Dna Methylation ◽

Correlation Coefficients ◽

Global Dna Methylation ◽

Site Specific ◽

Cpg Sites ◽

Cpg Site ◽

Biological Pathway Analysis ◽

Exploratory Approach ◽

Health Related ◽

Related Pathway

The aim of this exploratory study was to investigate how sedentary behavior (SB) and physical activity (PA) influence DNA methylation at a global, gene-specific, and health-related pathway level. SB, light PA (LPA), and moderate-to-vigorous PA (MVPA) were assessed objectively for 41 Flemish men using the SenseWear Pro 3 Armband. CpG site-specific methylation in leukocytes was determined using the Illumina HumanMethylation 450 BeadChip. Correlations were calculated between time spent on the three PA intensity levels and global DNA methylation, using a z-score-based method to determine global DNA methylation levels. To determine whether CpG site-specific methylation can be predicted by these three PA intensity levels, linear regression analyses were performed. Based on the significantly associated CpG sites at α = 0.005, lists were created including all genes with a promoter region overlapping these CpG sites. A biological pathway analysis determined to what extent these genes are overrepresented within several pathways. No significant associations were observed between global DNA methylation and SB (r = 0.084), LPA (r = -0.168), or MVPA (r = -0.125), although the direction of the correlation coefficients is opposite to what is generally reported in literature. SB has a different impact on global and gene-specific methylation than PA, but also LPA and MVPA affect separate genes and pathways. Furthermore, the function of a pathway seems to determine its association with SB, LPA, or MVPA. Multiple PA intensity levels, including SB, should be taken into account in future studies investigating the effect of physical (in)activity on human health through epigenetic mechanisms.

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Very High Weight Gain During Exclusive Breastfeeding Followed by Slowdown During Complementary Feeding: Two Case Reports

Journal of Human Lactation ◽

10.1177/0890334418756580 ◽

2018 ◽

Vol 35 (1) ◽

pp. 44-48 ◽

Cited By ~ 4

Author(s):

Melanie Wange Larsson ◽

Anni Larnkjær ◽

Sophie Hilario Christensen ◽

Christian Mølgaard ◽

Kim F. Michaelsen

Keyword(s):

Weight Gain ◽

Exclusive Breastfeeding ◽

Complementary Feeding ◽

High Weight ◽

Case Reports ◽

High Weight Gain ◽

Very High

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DNA methylation partially mediates the relationship between childhood adversity and depressive symptoms in adolescence

10.1101/2021.06.28.21259426 ◽

2021 ◽

Author(s):

Brooke J. Smith ◽

Alexandre A Lussier ◽

Janine Cerutti ◽

Daniel J. Schaid ◽

Andrew J. Simpkin ◽

...

Keyword(s):

Dna Methylation ◽

Depressive Symptoms ◽

Life Course ◽

Adolescent Depression ◽

Childhood Adversity ◽

Depression Symptoms ◽

Cpg Sites ◽

Cpg Site ◽

Sensitive Periods ◽

The Relationship

Background: Exposure to adversity during childhood is estimated to at least double the risk of depression later in life. Some evidence suggests childhood adversity may have a greater impact on depression risk, if experienced during specific windows of development called sensitive periods. During these sensitive periods, there is evidence that adversity may leave behind biological memories, including changes in DNA methylation (DNAm). Here we ask if those changes play a role in the link between adversity and later adolescent depressive symptoms. Methods: We applied a method for high-dimensional mediation analysis using data from a subsample (n=627-675) of the Avon Longitudinal Study of Parents and Children. We first assessed the possibility of time-dependent relationships between seven types of childhood adversity (caregiver abuse, physical/sexual abuse, maternal psychopathology, one-adult household, family instability, financial stress, neighborhood disadvantage), measured on at least four occasions between ages 0-7 years, and adolescent depression at mean age 10.6. Specifically, we considered three types of life course hypotheses (sensitive periods, accumulation, and recency), and then evaluated which of these hypotheses had the strongest association in each adversity-adolescent depression relationship using the structured life course modeling approach (SLCMA; pronounced slick-mah). To conduct the mediation analyses, we used a combination of pruning and sure independence screening (a dimension reduction method) to reduce the number of methylated CpG sites under consideration to a viable subset for our sample size. We then applied a sparse group lasso penalized model to identify the top mediating loci from that subset using the combined strength of the coefficient measuring the relationship between the childhood adversity and a CpG site (α) and of the coefficient measuring the relationship between the CpG site and depressive symptoms (β) as a metric. Using a Monte Carlo method for assessing mediation (MCMAM), we assigned a significance level and confidence interval to each identified mediator. Results: Across all seven adversities, we identified a total of 70 CpG sites that showed evidence of mediating the relationship between adversity and adolescent depression symptoms. Of these 70 mediators, 37 were significant at the p < 0.05 level when applying the MCMAM, a method tailored to estimating the significance of SEM-derived mediation effects. These sites exhibited four different mediating patterns, differentiated by the direction of α and β. These patterns had signals that were: (1) both positive (19 loci), (2) both negative (18 loci), (3) positive α and negative β (23 loci) or (4) negative α and positive β (10 loci). Conclusion: Our results suggest that DNAm partially mediates the relationship between different types of childhood adversity and depressive symptoms in adolescence. These findings provide insight into the biological mechanisms that link childhood adversity to depression, which will ultimately help develop treatments to prevent depression in more vulnerable populations.

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Infant adiposity at birth and early postnatal weight gain predict increased aortic intima-media thickness at 6 weeks of age: a population-derived cohort study

Clinical Science ◽

10.1042/cs20150685 ◽

2016 ◽

Vol 130 (6) ◽

pp. 443-450 ◽

Cited By ~ 11

Author(s):

Kate McCloskey ◽

David Burgner ◽

John B. Carlin ◽

Michael R. Skilton ◽

Michael Cheung ◽

...

Keyword(s):

Cohort Study ◽

Weight Gain ◽

Birth Weight ◽

Intima Media Thickness ◽

Birth Cohort Study ◽

Vascular Assessment ◽

Media Thickness ◽

Early Weight Gain ◽

Postnatal Weight Gain ◽

Aortic Intima

This is the first birth cohort study to analyse markers of infant adiposity, postnatal weight gain and early vascular assessment using aortic IMT. Increased birth weight, adiposity and early weight gain were associated with increased infant aortic intima-media thickness (aortic IMT).

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Correlation of Infinium HumanMethylation450K and MethylationEPIC BeadChip arrays in cartilage

10.1101/733204 ◽

2019 ◽

Author(s):

Kathleen Cheung ◽

Marjolein J. Burgers ◽

David A. Young ◽

Simon Cockell ◽

Louise N. Reynard

Keyword(s):

Dna Methylation ◽

Correlation Coefficient ◽

Whole Blood ◽

Pearson Correlation ◽

Cell Types ◽

Poor Correlation ◽

450K Array ◽

Human Cartilage ◽

Cpg Sites ◽

Cpg Site

AbstractBackgroundDNA methylation of CpG sites is commonly measured using Illumina Infinium BeadChip platforms. The Infinium MethylationEPIC array has replaced the Infinium Methylation450K array. The two arrays use the same technology, with the EPIC array assaying 865859 CpG sites, almost double the number of sites present on the 450K array. In this study, we compare DNA methylation values of shared CpGs of the same human cartilage samples assayed using both platforms.MethodsDNA methylation was measured in 21 human cartilage samples using the Illumina Infinium Methylation450K BeadChip and the Infinium methylationEPIC array. Additional matched 450K and EPIC data in whole tumour and whole blood were downloaded from GEO GSE92580 and GSE86833 respectively. Data were processed using the Bioconductor package Minfi. Additionally, DNA methylation of six CpG sites was validated for the same 21 cartilage samples by use of pyrosequencing.ResultsIn cartilage samples, overall sample correlations between methylation values generated by the two arrays were high (Pearson correlation coefficient r > 0.96). However, 50.5% of CpG sites showed poor correlation (r < 0.2) between arrays. Sites with limited variance and with either very high or very low methylation levels in cartilage exhibited lower correlation values, corroborating prior studies in whole blood. Bisulfite pyrosequencing did not highlight one array as generating more accurate methylation values that the other. For a specific CpG site, the array methylation correlation coefficient differed between cartilage, tumour and whole blood, reflecting the difference in methylation variance between cell types. These patterns can be observed across different tissues with different CpG site variances. When performing differential methylation analysis, the mean probe correlation co-efficient increased with increasing Δβ threshold used.ConclusionCpG sites with low variability within a tissue showed poor reproducibility between arrays. However, variance and thus reproducibility differs across different tissue types. Therefore, researchers should be cautious when analysing methylation of CpG sites that show low methylation variance within the cell type of interest, regardless of platform or method used to assay methylation.

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