Cord blood co-methylation network mediates the association between prenatal diet and cognition at age 2 years: A birth cohort study

In pregnancy, wholefood diets with an anti-inflammatory profile may influence long-term brain development through epigenetic modifications, particularly DNA methylation. Since DNA methylation signatures associated with children’s cognition and language development are likely multifactorial, an advanced epigenetic network approach is required to assess multiple CpG patterns and their underlying influences. Here we investigated a cognition-related co-methylation (Co-MN ^cog1 ) network using weighted gene co-expression network analysis. Genes significantly enriched in the Co-MN ^cog1 network were related to neural function, plasticity and synapse formation. Using a longitudinal population-derived cohort (Barwon Infant Study, N=562 mother-child pairs), we found that the maternal wholefood dietary pattern was associated with a higher Co-MN ^cog1 network (p=0.001) and higher offspring Bayley-III cognitive scores (p<0.001). Conversely, a higher prenatal maternal dietary inflammatory index was associated with a lower Co-MN ^cog1 network (p=0.005) and lower offspring cognitive score (p<0.001). The Co-MN ^cog1 network partially mediated the following associations: (i) higher prenatal wholefood dietary pattern and higher children’s cognitive (percentage mediated=10%, p=0.038) and receptive language (percentage mediated=7%, p=0.042) scores at age 2 years, and (ii) higher prenatal dietary inflammatory index and lower children’s cognitive (percentage mediated=9%, p=0.050) and receptive language (percentage mediated=8%, p=0.040) scores at age 2 years. Importantly, we confirmed that the Co-MN ^cog1 network was associated (p=0.015) with children’s Bayley-III social-emotional outcomes at age 2 years in an external cohort. These results highlight the central role of prenatal diet in shaping children’s cognition, language and social-emotional development through epigenetic modification, and identified possible pathways implicated in fetal neurodevelopment.