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

Luhang Han,A John Henderson,S Hasan Arshad,Susan L Ewart,John W Holloway,Susan Ring,Wilfried Karmaus,Latha Kadalayil,Akhilesh Kaushal,Hongmei Zhang,Caroline L Relton,Faisal I Rezwan

doi:10.1186/s13148-019-0780-4

Abstract

BackgroundAdolescence 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.MethodsGenome-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.ResultsIn 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.ConclusionAdolescent 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.

Highlights

Adolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M)
Results from the Isle of Wight (IOW) birth cohort At the genome-scale, medians of DNA-M at all Multiple CpG (CpGs) indicated that DNA-M at age 18 tended to be higher than that at age 10 years for both genders, but at age 18 DNA-M of females overall was higher than that of males (Table 1)
Using linear mixed models with gender and time interaction effects included (Model 2), we identified at 1179 CpGs (FDR = 0.05; Additional file 1), where DNA-M changes across adolescence were genderspecific (Fig. 2a)

Summary

Introduction

Adolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M). 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 adolescencerelated factors are associated with changes in DNA-M. The time period from pre-adolescence to postadolescence is denoted as the adolescence transition period, during which children experience significant gender-dependent social, environmental, and physiological changes, e.g., transition to independence, initiation of smoking, puberty, rapid growth, and often body mass index (BMI) increase [1,2,3,4]. In addition to physiological changes, preand post-adolescence transition has been linked to changes in disease status for conditions such as asthma, emphasizing the importance of this critical transition period to life-long health. Through epigenetic regulation of gene activity, DNA-M is associated with disease susceptibility directly, or through synergistic effects with single nucleotide polymorphisms [15,16,17]

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Conclusion