Sex-Specific Cord Blood DNA Methylation Signatures for Childhood ADHD Symptoms
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The underdiagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) in females, particularly those with the inattentive presentation, highlights a critical gap in clinical care. While DNA methylation may be tissue-specific, accessible peripheral measures such as cord blood can provide valuable insights into early-life risk and serve as potential biomarkers for detection. We aimed to discover sex-specific epigenetic markers in cord blood associated with childhood ADHD symptoms, which could illuminate early-life risk mechanisms and inform improved detection strategies.
Method
We conducted sex-stratified epigenome-wide association study (EWAS) of cord blood DNA methylation in relation to ADHD symptoms among child participants (n=2,417; 47% females) of the Norwegian Mother, Father, and Child study (MoBa). We tested for sex-interaction effects and analyzed inattention and hyperactivity/impulsivity symptoms separately.
Results
We identified 21 differentially methylated CpG positions (DMPs). The majority (n=13) were associated with inattention symptoms exclusively in females, and all exhibited significant sex-interaction effects (corrected p -value <0.05). There was no overlap between the DMPs, or differentially methylated regions (DMRs) identified in females and males, and the epigenetic signatures for inattention and hyperactivity/impulsivity were largely distinct. Several annotated genes (e.g., PNPO, KDM5B , and GABRP ) have recognized roles in neurotransmission and neurodevelopment.
Conclusion
Our findings demonstrate that the peripheral epigenetic profile at birth associated with later ADHD is remarkably different between sexes. This highlights the value of sex-stratified analyses and suggests that peripheral epigenetic markers hold promise for the development of tools for early detection.
