Epigenetic signature of very low birth weight in young adult life

Abstract

Background: Globally, one in ten babies is born preterm (<37 weeks), and 1-2% preterm at very low birth weight (VLBW, <1500 g). As adults, they are at increased risk for a plethora of health conditions, e.g., cardiometabolic disease, which may partly be mediated by epigenetic regulation. We compared blood DNA methylation between young adults born at VLBW and controls.

Methods: 157 subjects born at VLBW and 161 controls born at term, from the Helsinki Study of Very Low Birth Weight Adults, were assessed for peripheral venous blood DNA methylation levels at mean age of 22 years. Significant CpG-sites (5'-C-phosphate-G-3') were meta-analyzed against continuous birth weight in four independent cohorts (pooled n = 2235) with cohort mean ages varying from 0 to 31 years.

Results: In the discovery cohort, 66 CpG-sites were differentially methylated between VLBW adults and controls. Top hits were located in HIF3A, EBF4, and an intergenic region nearest to GLI2 (distance 57,533 bp). Five CpG-sites, all in proximity to GLI2, were hypermethylated in VLBW and associated with lower birth weight in the meta-analysis.

Conclusion: We identified differentially methylated CpG-sites suggesting an epigenetic signature of preterm birth at VLBW present in adult life.

Impact: Being born preterm at very low birth weight has major implications for later health and chronic disease risk factors. The mechanism linking preterm birth to later outcomes remains unknown. Our cohort study of 157 very low birth weight adults and 161 controls found 66 differentially methylated sites at mean age of 22 years. Our findings suggest an epigenetic mark of preterm birth present in adulthood, which opens up opportunities for mechanistic studies.

Fig. 1. Manhattan plot of the epigenome-wide association study for the discovery cohort.

The analysis was adjusted for sex, age, cell type proportions, maternal smoking during pregnancy, and parental socioeconomic status. The x-axis is the chromosomal position, and the y-axis is the level of statistical significance on a −log₁₀-scale. The blue line represents the threshold for experiment wide significance at p = 7.6 × 10⁻⁶. CpGs highlighted in green represent sites with an epigenome wide significance of p < 9 × 10⁻⁸ (red line). The thresholds are based on previous recommendations.^,

Fig. 2. Quantile-quantile plot of the distribution.

The observed association p values are plotted against the expected null distribution for the discovery analysis.

Fig. 3. Forest plots showing meta-analysis of significant DNA methylation betas.

Meta-analysis of DNA methylation betas is shown for birth weight (kg) at CpGs across four studies (PREDO, GLAKU, NFBC1986, and NFBC1966) with 95% confidence intervals after FDR-correction by Benjamini-Hochberg method at level 0.05. Adjusted for age, sex, maternal smoking during pregnancy, parental education, technical covariates, and cell type proportions.