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Impact of SNAP-25 MnlI polymorphism on brain activity patterns in children with ADHD: Insights from fractional amplitude of low-frequency fluctuation analysis

Year: 2026

Type: article

Abstract: SNAP-25, a synaptic vesicle docking protein, carries a polymorphism (rs3746544) in its 3′-UTR region that is associated with ADHD, yet its functional mechanism remains unknown. The purpose of this study is to evaluate the impact of synaptosomal-associated protein 25 (SNAP-25) gene MnlI polymorphism (rs3746544) on spontaneous brain activity in children with attention deficit hyperactivity disorder (ADHD), employing the fractional amplitude of low-frequency fluctuation (fALFF) analysis of resting-state functional Magnetic Resonance Imaging (rs-fMRI) data, to explore its potential neurobiological mechanisms and neuroimaging biomarkers. This study enrolled 56 boys with ADHD (aged 8–10 years) and 21 age-matched healthy boys as healthy controls (HCs). According to the SNAP-25 MnlI genotype, ADHD patients were divided into two groups: the TT homozygote group (TT group, n = 36) and the G-allele carrier group (TG group, n = 20). Rs-fMRI data were acquired and analyzed using fALFF to measure spontaneous brain activity. One-sample t -tests were performed to calculate fALFF maps for each group, setting the threshold as a cluster greater than 20 voxels, with P < 0.01 after AlphaSim correction. Two-sample t -tests were performed to calculate the differences in fALFF values among the TT, TG, and HCs groups, with age as a covariate. A cluster of greater than 20 voxels, with P < 0.01 after AlphaSim correction, was considered to have statistically significant differences. Assessed the Working Memory Index (WMI) using the Wechsler Intelligence Scale for Children-IV (WISC-IV) in children with ADHD from the TT and TG groups. One-sample t -tests revealed that children with ADHD group (both TT and TG group) exhibited significantly lower fALFF values in the default mode network (DMN) and parieto-occipital cortex compared to HCs, while showing increased fALFF located in the posterior cerebellar lobe; Two-sample t -tests demonstrated that: (a) Compared to HCs, the ADHD group (both TT and TG group) showed widespread reductions of fALFF values across multiple brain regions, including the posterior cingulate cortex and precuneus. The TG group showed more pronounced decreases when compared with the TT group. (b) In comparison to the TG group, the TT group exhibited higher fALFF values in higher-order cognitive regions, such as the right superior frontal gyrus and left medial frontal gyrus, but lower fALFF values in the posterior cerebellar lobe and posterior cingulate cortex. The TT group had significantly higher WMI compared to the TG group ( t = 2.098, P < 0.05). The SNAP-25 gene MnlI polymorphism has an impact on spontaneous brain activity in children with ADHD, as measured by fALFF. This study reveals the potential mechanisms from the perspective of brain networks, demonstrates how ADHD genotypes affect neural function, and provides a new approach for clinical decision-making and efficacy monitoring. • Genotype-Specific Differences : Compared to G-allele carriers, TT homozygotes showed enhanced activity in the right superior frontal and left medial frontal gyri, but reduced activity in the posterior cerebellar lobe and posterior cingulate cortex. • Cognitive Performance : TT homozygotes had significantly higher Working Memory Index (WMI) scores, indicating superior cognitive performance. • Neurobiological Mechanisms : The SNAP-25 MnlI polymorphism may influence cognition by modulating the frontoparietal executive network and the default mode network (DMN).

Source: Neuroimage Reports

DOI: 10.1016/j.ynirp.2026.100321