Epigenetic and Brain Structure Covariation Patterns in Typical and Atypical Development

Abstract

By studying changes in gene expression that occur without altering the DNA sequence, epigenetics offers a promising lead in unraveling how biological factors interact with the environment to shape brain development. However, prior developmental studies have focused on candidate brain or epigenetic regions, limiting our understanding of brain‐ and epigenome‐wide links during childhood. This study explored associations between brain‐wide structural imaging (T1‐weighted, diffusion‐weighted) and epigenome‐wide DNA methylation in 144 children with and without ADHD, using parallel Independent Component Analysis (pICA) to identify linked patterns. We identified five significantly linked brain–epigenome components, in which methylation explains a significant proportion of variance in associated brain components, and further pinpointed 908 CpGs as part of the strongest epigenetic–brain associations using multivariate random forest analysis. Genes linked to these CpGs were enriched in neuronal development and associated with psychiatric/neurodevelopmental disorders, underscoring their functional relevance. Exploratory analyses suggested that ADHD diagnosis and demographic variables may modulate these brain–epigenome associations. Our study links brain anatomy to DNA methylation patterns in functionally relevant genes involved in neuronal development and psychiatric disorders, highlighting potential biological insights through which genetic and environmental factors may influence brain development. We further provide epigenetic to brain cluster mappings and a companion script to extract epigenetic–brain links, offering resources for future neurodevelopmental studies.