Sex differences in DNA methylation of the cord blood are related to sex-bias psychiatric diseases

Abstract

Sex differences in the prevalence of psychiatric disorders are well documented, with exposure to stress during gestation differentially impacting females and males. We explored sex-specific DNA methylation in the cord blood of 39 females and 32 males born at term and with appropriate weight at birth regarding their potential connection to psychiatric outcomes. Mothers were interviewed to gather information about environmental factors (gestational exposure) that could interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. Excluding XYS probes, there were 2,332 differentially methylated CpG sites (DMSs) between sexes, which were enriched within brain modules of co-methylated CpGs during brain development and also differentially methylated in the brains of boys and girls. Genes associated with the DMSs were enriched for neurodevelopmental disorders, particularly for CpG sites found differentially methylated in brain tissue between patients with schizophrenia and controls. Moreover, the DMS had an overlap of 890 (38%) CpG sites with a cohort submitted to toxic exposition during gestation. This study supports the evidences that sex differences in DNA methylation of autosomes act as a primary driver of sex differences that are found in psychiatric outcomes.

Figure 1. Characterization of the differentially methylated CpG sites between females and males.

Volcano plot of the differential methylation analysis with X and Y axes displaying, respectively, the delta-beta values and the log10 of adjusted p-values for each CpG site. CpGs more methylated in females and males are represented in pink and blue, respectively.

Figure 2. Enrichment analysis for the modules from Parikshak et al., that identified genes co-expressed during cortical development.

Graphs show the distribution of genes related to the studies in enriched modules (p < 0.05). Scatter smooth of module eigengene values was defined by Parikshak et al. at different stages of neocortical development. Different periods of lifetime are scaled from light to dark blue colors: early foetal, early-mid foetal, late midfoetal, late foetal, neonatal/early infancy and late infancy. The red line indicates time of birth. Sets of genes enriched for the modules are displayed below of each graph.