Dataset Information

Changes in DNA methylation from pre- to post-adolescence are associated with pubertal exposures.

ABSTRACT:

Background

Adolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M). However, it is unknown to what extent DNA-M varies from pre- to post-adolescence, whether the pattern of changes is different between females and males, and how adolescence-related factors are associated with changes in DNA-M.

Methods

Genome-scale DNA-M at ages 10 and 18 years in whole blood of 325 subjects (n = 140 females) in the Isle of Wight (IOW) birth cohort was analyzed using Illumina Infinium arrays (450K and EPIC). Linear mixed models were used to examine DNA-M changes between pre- and post-adolescence and whether the changes were gender-specific. Adolescence-related factors and environmental exposure factors were assessed on their association with DNA-M changes. Replication of findings was attempted in the comparable Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

Results

In the IOW cohort, after controlling for technical variation and cell compositions at both pre- and post-adolescence, 15,532 cytosine-phosphate-guanine (CpG) sites (of 400,825 CpGs, 3.88%) showed statistically significant DNA-M changes from pre-adolescence to post-adolescence invariant to gender (false discovery rate (FDR) = 0.05). Of these 15,532 CpGs, 10,212 CpGs (66%) were replicated in the ALSPAC cohort. Pathway analysis using Ingenuity Pathway Analysis (IPA) identified significant biological pathways related to growth and development of the reproductive system, emphasizing the importance of this period of transition on epigenetic state of genes. In addition, in IOW, we identified 1179 CpGs with gender-specific DNA-M changes. In the IOW cohort, body mass index (BMI) at age 10 years, age of growth spurt, nonsteroidal drugs use, and current smoking status showed statistically significant associations with DNA-M changes at 15 CpGs on 14 genes such as the AHRR gene. For BMI at age 10 years, the association was gender-specific. Findings on current smoking status were replicated in the ALSPAC cohort.

Conclusion

Adolescent transition is associated with changes in DNA-M at more than 15K CpGs. Identified pathways emphasize the importance of this period of transition on epigenetic state of genes relevant to cell growth and immune system development.

SUBMITTER: Han L

PROVIDER: S-EPMC6888960 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundThe pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood.MethodsDNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex.ResultsHigh and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases.ConclusionThe identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.

Project description:BackgroundAdolescence is a significant period for the gender-dependent development of lung function. Prior studies have shown that DNA methylation (DNA-M) is associated with lung function and DNA-M at some cytosine-phosphate-guanine dinucleotide sites (CpGs) changes over time. This study examined whether changes of DNA-M at lung-function-related CpGs are associated with changes in lung function during adolescence for each gender, and if so, the biological significance of the detected CpGs.MethodsGenome-scale DNA-M was measured in peripheral blood samples at ages 10 (n = 330) and 18 years (n = 476) from the Isle of Wight (IOW) birth cohort in United Kingdom, using Illumina Infinium arrays (450 K and EPIC). Spirometry was conducted at both ages. A training and testing method was used to screen 402,714 CpGs for their potential associations with lung function. Linear regressions were applied to assess the association of changes in lung function with changes of DNA-M at those CpGs potentially related to lung function. Adolescence-related and personal and family-related confounders were included in the model. The analyses were stratified by gender. Multiple testing was adjusted by controlling false discovery rate of 0.05. Findings were further examined in two independent birth cohorts, the Avon Longitudinal Study of Children and Parents (ALSPAC) and the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort. Pathway analyses were performed on genes to which the identified CpGs were mapped.ResultsFor females, 42 CpGs showed statistically significant associations with change in FEV1/FVC, but none for change in FEV1 or FVC. No CpGs were identified for males. In replication analyses, 16 and 21 of the 42 CpGs showed the same direction of associations among the females in the ALSPAC and BAMSE cohorts, respectively, with 11 CpGs overlapping across all the three cohorts. Through pathway analyses, significant biological processes were identified that have previously been related to lung function development.ConclusionsThe detected 11 CpGs in all three cohorts have the potential to serve as the candidate epigenetic markers for changes in lung function during adolescence in females.

Project description:Phthalates are a class of endocrine disrupting chemicals with near ubiquitous exposure to populations around the world. Phthalates have been associated with children's adiposity in previous studies, though discrepancies exist across studies that may be due to timing of exposure or outcome assessment and population differences (i.e., genetics, other confounders). DNA methylation, an epigenetic modification involved in gene regulation, may mediate the effects of early life phthalate exposures on health outcomes. This study aims to evaluate the mediating effect of DNA methylation at growth-related genes on the association between phthalate exposure and repeat measures of adiposity (BMI-for-age z-score, waist circumference, and skinfolds thickness) in Mexican children. Urinary phthalate metabolite concentrations were quantified in mothers at each of the three trimesters of pregnancy and in children at the first peri-adolescent study visit. Blood leukocyte DNA methylation at H19 and HSD11B2 was quantified during the first peri-adolescent visit, and adiposity was measured at the first visit and again ~3 years later among participants (n = 109 boys, 114 girls) from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) project. Associations between phthalates or DNA methylation and repeat outcome measures were assessed separately in boys and girls using generalized estimating equation models including covariates (urinary specific gravity, maternal education, and child's age). Sobel tests were used to assess DNA methylation as a mediator in models adjusting for the same covariates. Associations between phthalates and adiposity varied by phthalate and timing of exposure. Early gestation MBP, MIBP, and MBzP were associated with adiposity among girls. For example, among girls first trimester maternal urine concentrations of MIBP were associated with increases in skinfold thickness, BMI-for-age, and waist circumference (p < 0.01). Second trimester and adolescent MBzP were associated with adiposity among boys in opposite directions. In girls, H19 methylation was positively associated with skinfold thickness. No significant mediation of phthalate exposure on adiposity by DNA methylation of H19 or HSD11B2 was observed (Sobel p > 0.05). However, the mediation analysis was underpowered to detect small to medium effect sizes, and the role of DNA methylation as a mediator between phthalates and outcomes merits further study.