DNA methylation patterns in cord blood DNA and body size in childhood

Abstract

Background: Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood.

Principal findings: A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood. Gene expression analysis was undertaken in 24 individuals whose biological samples and clinical data were collected at a mean ± standard deviation (SD) age of 12.35 (0.95) years, the upper and lower tertiles of body mass index (BMI) were compared with a mean (SD) BMI difference of 9.86 (2.37) kg/m(2). This generated a panel of differentially expressed genes for DNA methylation analysis which was then undertaken in cord blood DNA in 178 individuals with body composition data prospectively collected at a mean (SD) age of 9.83 (0.23) years. Twenty-nine differentially expressed genes (>1.2-fold and p<10(-4)) were analysed to determine DNA methylation levels at 1-3 sites per gene. Five genes were unmethylated and DNA methylation in the remaining 24 genes was analysed using linear regression with bootstrapping. Methylation in 9 of the 24 (37.5%) genes studied was associated with at least one index of body composition (BMI, fat mass, lean mass, height) at age 9 years, although only one of these associations remained after correction for multiple testing (ALPL with height, p(Corrected) = 0.017).

Conclusions: DNA methylation patterns in cord blood show some association with altered gene expression, body size and composition in childhood. The observed relationship is correlative and despite suggestion of a mechanistic epigenetic link between in utero life and later phenotype, further investigation is required to establish causality.

Figure 1. Overview of study design.

Gene expression analysis was conducted on RNA samples collected at age 11–13 years when children in the Preterm Birth Growth Study (PTBGS) attended clinical assessment which included body composition measurement. Genes highlighted as being differentially expressed in relation to high/low BMI in this study group were then analysed in cord blood DNA samples from the Avon Longitudinal Study of Parents and Children (ALSPAC). Methylation levels were then analysed in relation to later body composition assessments carried out at 9 years in this study group.

Figure 2. Distribution of methylation-phenotype associations.

Distribution of −log₁₀ p-values for bootstrap analysis of BMI and DNA methylation in cord blood DNA according to mean methylation levels at the 44 CpG sites analysed.