Genetic Interplay Between Attention-Deficit/Hyperactivity Disorder and Pain Suggests Neurodevelopmental Pathways and Comorbidity Risk.

Background: In this study, we investigated the genetic connections between attention-deficit/hyperactivity disorder (ADHD), migraine (MGN), and multisite chronic pain (MCP). The goal was to identify specific shared biological mechanisms that contribute to the overlap between ADHD and these pain-related conditions. Methods: We utilized various post-genome-wide association study analyses on summary data from samples ranging between 225,534 and 766,345 individuals. In an independent sample of patients with ADHD and control participants (665 cases and 995 controls), we evaluated MGN and MCP polygenic risk scores (PRSs) in relation to comorbid profiles, symptom severity, and neuroimaging brain scores. Results: The findings show a strong biological overlap between ADHD and MCP, with a less pronounced relationship with MGN. Key regions and genes associated with ADHD and MCP were enriched in neurodevelopmental pathways, including those involved in neuron projection morphogenesis and nervous system development. Drug-set enrichment analysis identified that some of these pathways are potentially influenced by paracetamol, a drug that has been implicated as a class I environmental risk factor for ADHD when exposure occurs prenatally. Causal inference analysis using a 5-fold larger ADHD summary dataset demonstrated stronger effects of MCP on ADHD than the reverse. In the independent sample, higher MCP PRSs were linked to structural brain features, increased comorbidity with substance use and bipolar disorder, and heightened severity of ADHD symptoms. Conclusions: These findings underscore the significant genetic relationship between ADHD and MCP, suggesting that shared genetic factors may influence brain development and contribute to diverse clinical outcomes in ADHD.