Socioeconomic position during pregnancy and DNA methylation signatures at three stages across early life: epigenome-wide association studies in the ALSPAC birth cohort

Abstract

Background: Socioeconomic experiences are recognized determinants of health, and recent work has shown that social disadvantages in early life may induce sustained biological changes at molecular level that are detectable later in life. However, the dynamics and persistence of biological embedding of socioeconomic position (SEP) remains vastly unexplored.

Methods: Using the data from the ALSPAC birth cohort, we performed epigenome-wide association studies of DNA methylation changes at three life stages (birth, n = 914; childhood at mean age 7.5 years, n = 973; and adolescence at mean age 15.5 years, n = 974), measured using the Illumina HumanMethylation450 Beadchip, in relation to pregnancy SEP indicators (maternal and paternal education and occupation).

Results: Across the four early life SEP metrics investigated, only maternal education was associated with methylation levels at birth, and four CpGs mapped to SULF1, GLB1L2 and RPUSD1 genes were identified [false discovery rate (FDR)-corrected P-value <0.05]. No epigenetic signature was found associated with maternal education in child samples, but methylation levels at 20 CpG loci were found significantly associated with maternal education in adolescence. Although no overlap was found between the differentially methylated CpG sites at different ages, we identified two CpG sites at birth and during adolescence which are 219 bp apart in the SULF1 gene that encodes an heparan sulphatase involved in modulation of signalling pathways. Using data from an independent birth cohort, the ENVIRONAGE cohort, we were not able to replicate these findings.

Conclusions: Taken together, our results suggest that parental SEP, and particularly maternal education, may influence the offspring's methylome at birth and adolescence.

Keywords: DNA methylation; Social class; education; occupations.

Figure 1.

Study workflow. The figure depicts the study workflow which is structured in three phases. First, the association between DNA methylation levels at birth and the four indicators of early life SEP was investigated performing EWAS (1 A1) and then regressing DNA methylation PCs against each indicators of SEP (1 A2). Second, based on significance from the PC analyses, a SEP indicator was selected. EWASs were performed for this selected indicator and DNA methylation status at childhood (1 B1) and at adolescence (1 B2), and methylation levels of the probes significant in cord blood were integrated over the three time points in a longitudinal model (1 B3). Finally, we adopted a targeted approach to seek independent validation of the CpG sites differentially methylated in relation to the selected SEP indicator both at birth and later in life, using neonatal biosamples from the ENVIRONAGE study (1 C1). EWAS, epigenome-wide association study; PCA, principal component analysis; SEP, socioeconomic position.

Figure 2.

Volcano plots for EWAS of parental early life SEP indicators and cord DNA methylation. The figure shows the volcano plots for EWAS of cord DNA methylation and parental early life SEP indicators (2A, maternal education; 2B, paternal education; 2C, maternal occupation; 2D, paternal occupation). β values (coefficients) are reported on the x-axis as a function of the −log10 P-values on the y-axis. The horizontal line represents the FDR level of 0.05. CpG sites whose methylation levels were found statistically differentially methylated in the analysis of maternal education are highlighted in black, and located also in the plots of maternal occupation and paternal education and occupation. Models were adjusted for birthweight, parity, gestational age and sex of the newborn in addition to technical variables: bead array row and bisulphite conversion batch.

Figure 3.

Delta rank of the top 100 CpG loci for the four SEP indicators. The upper part of the plot represents the difference in the rank of the first 100 CpG loci from the EWAS of (3A) maternal and (3B) paternal education and the rank of the same CpG loci in the EWAS of the other SEP indicators in cord blood identified by colours and shapes of the dots (maternal education, cross; paternal education, plus; maternal occupation, circle; paternal occupation, triangle). The lower part of the plot (3C) shows the correlation plot of the first 100 strongest associations from the EWAS of maternal and paternal education in cord blood. Ranks are derived from models adjusted for birthweight, parity, gestational age and sex of the newborn in addition to technical variables: bead array row and bisulphfite conversion batch. EF, education of the father; OM, occupation of the mother; OF, occupation of the father; EM, education of the mother.

Figure 4.

Heatmap of associations between SEP indicators and principal components of cord blood DNA methylation. The heatmap depicts the estimates of associations, represented by shades, and corresponding P-values, displayed as numbers, between the four SEP indicators and the first five principal components of cord blood DNA methylation. Models were adjusted for birthweight, parity, gestational age and sex of the newborn in addition to technical variables: bead array row and bisulphite conversion batch. EF, education of the father; EM, education of the mother; OF, occupation of the father; OM, occupation of the mother.