The Association Between EPHA5 Gene Polymorphism and Attention-Deficit/Hyperactivity Disorder Based on the "Gene-Brain-Cognition" Model

Based on the "gene-brain-cognition" model, this study aimed to investigate the association between the rs4860671 polymorphism of the EPHA5 gene and attention-deficit/hyperactivity disorder (ADHD), and to analyze its impact on executive function and resting-state brain activity in affected children.

This was a case-control study. Children with ADHD attending the outpatient clinic of Peking University Sixth Hospital from 2015 to 2020 and typically developing children from general primary and secondary schools in Beijing during the same period were enrolled as subjects. Genotypes of the EPHA5 rs4860671 polymorphism were determined in both groups. Resting-state functional magnetic resonance imaging was used to assess spontaneous brain activity. In addition, the ADHD Rating Scale and the Behavior Rating Inventory of Executive Function were administered to evaluate ADHD core symptoms and executive function, respectively. Genetic association analysis, analysis of covariance, and mediation analysis were systematically performed to explore the associations of the rs4860671 polymorphism with ADHD clinical symptoms, executive function, and brain functional activity.

A total of 244 children with ADHD and 83 healthy controls were included. Among them, 188 children with ADHD and 70 healthy controls completed MRI scanning. Allelic analysis revealed that the frequency of the G allele of rs4860671 was significantly higher in children with ADHD than in healthy controls (77.5% vs. 69.9%, P=0.049). Genotype distribution analysis also demonstrated a significant difference between the two groups under the dominant model (P=0.031). Regarding executive function, children carrying the GG genotype of rs4860671 had higher scores in emotion control compared with those carrying the A allele (AA+AG) (15.99±4.62 vs. 14.53±4.03, P=0.017), indicating poorer emotion regulation ability. Further mediation analysis showed that emotion control fully mediated the relationship between rs4860671 genotype and core symptoms of ADHD. Neuroimaging analysis revealed that among children with ADHD, carriers of the GG genotype exhibited decreased spontaneous brain activity in the right inferior occipital gyrus and left middle occipital gyrus compared with A allele carriers.

The rs4860671 polymorphism of the EPHA5 gene may be involved in the pathogenesis of ADHD by influencing emotion regulation ability and visual network functional activity. This finding provides new scientific evidence for a deeper understanding of the neurobiological mechanisms underlying ADHD.