Shared biological pathways linking ADHD and cortisol variability are related to externalizing behaviors

Area of Science:

• Neurogenetics
• Endocrinology
• Psychiatry

Background:

• Altered cortisol regulation is linked to Attention-Deficit/Hyperactivity Disorder (ADHD), but causal relationships are unclear.
• Existing meta-analyses suggest a correlation between lower morning cortisol levels and ADHD, though study heterogeneity exists.

Purpose of the Study:

• To investigate the causal relationship and shared genetic architecture between morning cortisol levels and ADHD using advanced genetic methods.
• To explore the role of specific genetic regions and polygenic scores in the association between cortisol and ADHD.

Main Methods:

• Employed Mendelian Randomization (MR) with seven methods on large-scale genetic data for morning cortisol (n=25,314) and ADHD (n=225,543).
• Assessed global and local genetic correlations, utilized the conjFDR method, and performed polygenic score (PGS) analysis in an independent ADHD sample (n=1660).

Main Results:

• Evidence suggests regional pleiotropy, not direct causality, with shared genomic architecture between morning cortisol and ADHD.
• Identified local genetic correlations on chromosomes 5 and 22, involving genes like RASGRF2 and TRIOBP.
• Cortisol PGS linked to externalizing behavior comorbidity in European ancestry and showed lower values in ADHD cases when adjusted for psychiatric disorders.

Conclusions:

• ADHD and cortisol levels are linked through complex arousal regulation, aligning with a U-shaped relationship model, rather than a simple stress-response mechanism.
• Findings support viewing ADHD as a systemic dysregulation, with implications for understanding its neurobiological underpinnings.
• Shared genetic factors contribute to the observed association, highlighting the intricate interplay between genetics and physiology in ADHD.