Sex-Specific Cord Blood DNA Methylation Signatures for Childhood ADHD Symptoms

BackgroundThe underdiagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) in females, particularly those with the inattentive presentation, highlights a critical gap in clinical care. Although DNA methylation is often tissue-specific, accessible peripheral tissues like cord blood provide valuable insights into early-life risk and can serve as biomarkers. We aimed to identify sex-specific DNA methylation signatures in cord blood associated with childhood ADHD symptoms, which could illuminate early-life risk markers and inform improved detection strategies. MethodWe conducted sex-stratified epigenome-wide association study (EWAS) of cord blood DNA methylation in relation to ADHD symptoms in children (n=2,391; 48.1% females) from the Norwegian Mother, Father, and Child cohort study (MoBa). We tested for sex interaction effects and analyzed inattention and hyperactivity/impulsivity symptoms separately. ResultsWe identified five differentially methylated CpG positions (DMPs) and 22 differentially methylated regions (DMRs). In females, two DMPs, cg13084029 (ARRB1) and cg15676735 (ZBTB3), and seven DMRs were associated with inattention symptoms. The identified DMPs exhibited significant sex interaction effects (adjusted p-value < 0.05). There was no overlap between the DMPs or DMRs identified in females and males, and the epigenetic signatures for inattention and hyperactivity/impulsivity were largely disparate. Several annotated genes (e.g., ARRB1, PNPO, KDM5B, HOXA2, and HOXC4) have recognized roles in neurotransmission and neurodevelopment. ConclusionOur findings demonstrate that the peripheral DNA methylation signatures at birth associated with later ADHD symptoms are distinct between females and males. This highlights the value of sex-stratified analyses and suggests that peripheral epigenetic profiles hold promise for the development of tools for early detection.