COMT genotype affects brain white matter pathways in attention-deficit/hyperactivity disorder

Abstract

Increased dopamine availability may be associated with impaired structural maturation of brain white matter connectivity. This study aimed to derive a comprehensive, whole-brain characterization of large-scale axonal connectivity differences in attention-deficit/hyperactivity disorder (ADHD) associated with catechol-O-methyltransferase gene (COMT) Val158Met polymorphism. Using diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach, we characterized altered white matter connectivity in youth with ADHD who were COMT Val-homozygous (N = 29) compared with those who were Met-carriers (N = 29). Additionally, we examined whether dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) polymorphisms were associated with white matter differences. Level of attention was assessed using the continuous performance test before and after an 8-week open-label trial of methylphenidate (MPH). A network of white matter connections linking 18 different brain regions was significantly weakened in youth with ADHD who were COMT Met-carriers compared to those who were Val-homozygous (P < 0.05, family-wise error-corrected). A measure of white matter integrity, fractional anisotropy, was correlated with impaired pretreatment performance in continuous performance test omission errors and response time variability, as well as with improvement in continuous performance test response time variability after MPH treatment. Altered white matter connectivity was exclusively based on COMT genotypes, and was not evident in DAT1 or DRD4. We demonstrated that white matter connectivity in youth with ADHD is associated with COMT Val158Met genotypes. The present findings suggest that different layers of dopamine-related genes and interindividual variability in the genetic polymorphisms should be taken into account when investigating the human connectome.

Children's academic attainment is linked to the global organization of the white matter connectome

“…The association between longer path length, reduced influence of hub nodes, and lower literacy and numeracy scores also resembles findings of atypical brain network organization following early insults like preterm birth, hypoxia‐ischaemia, and intra‐uterine growth restriction (Batalle et al., ; Pandit et al., ). Further, similar alterations in network organization were also linked to common genetic variants associated with neurodevelopmental disorders like autism and ADHD (Dennis et al., ; Hong et al., ). This may suggest that various developmental constraints converge on sub‐optimal brain network organization via various mechanisms and that these differences in brain network organization manifest in cognitive and behavioural symptoms commonly observed in developmental disorders.…”

The role of the structural connectome in literacy and numeracy development in children

“…Further, similar alterations in network organisation were also linked to common genetic variants associated with neurodevelopmental disorders like autism and ADHD (Dennis et al 2011, Hong et al 2014). This may suggest that various developmental constraints converge on sub-optimal brain network organisation via various mechanisms and that these differences in brain network organisation manifest in cognitive and behavioural symptoms commonly observed in developmental disorders.…”

The COMT Val158Met polymorphism moderates the association between cognitive functions and white matter microstructure in schizophrenia

“…Met carriers also showed larger WM hyperintensities in subcortical regions (Liu et al, 2014) and reduced intelligence-related FA in the corticospinal tract of healthy individuals (Liu et al, 2010). Finally, Met carriers showed reduced WM density in the cerebellum in velocardiofacial syndrome (Van Amelsvoort et al, 2008) and reduced WM connectivity in a network linking 18 different brain regions in patients with attention deficit hyperactivity disorder (Hong et al, 2015). Finally, Met carriers showed reduced WM density in the cerebellum in velocardiofacial syndrome (Van Amelsvoort et al, 2008) and reduced WM connectivity in a network linking 18 different brain regions in patients with attention deficit hyperactivity disorder (Hong et al, 2015).…”