The COMT Polymorphism and Cortical Thickness in ADHD

Post by Sarah Hill

What's the science?

How genetics relate to abnormal brain structure and function is currently an open question for researchers studying attention-deficit/hyperactivity disorder (ADHD). Research has suggested that a mutation in the catechol-O-methyltransferase (COMT) gene, a gene mediating dopamine signalling in the frontal cortex throughout neurodevelopment, is associated with altered gray matter volume in children with ADHD. However, which specific anatomical features and brain regions are related to COMT-associated gray matter abnormalities have yet to be determined. This week in Cerebral Cortex, Jung and colleagues report that the COMT mutation is specifically associated with differences in cortical thickness and surface area between children with and without ADHD.

How did they do it?

The authors used machine-learning methods to investigate whether cortical thickness and surface area were altered in children with ADHD and COMT gene mutations. First, they gathered MRI images from 39 boys with ADHD and 34 typically developing boys, all between the ages of 7 and 15, along with working memory scores for each participant. Next, they preprocessed the brain imaging data to acquire information on cortical thickness, surface area, and volume across 148 brain regions. This information was then classified by a machine-learning model trained to differentiate between brain imaging features in ADHD and typically developing groups [support vector machine-recursive feature elimination (SVM-RFE)]. The authors also analyzed differences in brain organization between the ADHD and typically developing groups using a specialized statistical method for assessing how gray matter structure co-varies across brain regions and individuals (i.e. structural covariance analysis). Finally, each participant was tested for the COMT Val158Met polymorphism, a COMT mutation previously implicated in ADHD, and the resulting four groups (ADHD/mutation-carrying, ADHD/normal COMT, typically developing/mutation-carrying, and typically developing/normal COMT) were compared for neuroanatomical and behavioral differences.

What did they find?

First, the authors found that the cortical thickness classifier (a model using cortical thickness to classify differences between groups) had the highest rate of accuracy (79%) compared to the surface area (74%) and volume (66%) classifiers, suggesting that cortical thickness may be a better predictor of neurodevelopmental disorder than cortical volume. They observed increased cortical thickness in the ADHD group across 16 brain areas relative to the typically developing group, with the most robust increase identified in the orbitofrontal cortex, a region involved in executive functions such as decision-making, reinforcement learning, and working memory. In contrast, cortical surface area was decreased in the ADHD group across 11 regions primarily throughout the frontal and temporal lobes. After further dividing of the two diagnostic groups based on COMT genotype, they next found that the mutation in ADHD subjects accounted for reduced cortical surface area, specifically in the left orbital sulcus (OrbS) (in the orbitofrontal cortex) compared to ADHD subjects with no COMT mutation. In typically developing participants, however, the COMT mutation was associated with decreased cortical thickness in the left orbital inferior frontal gyrus (oIFG) (also in the orbitofrontal cortex) relative to the three other groups. Finally, both the OrbS and oIFG measures negatively correlated with working memory score in ADHD children carrying the COMT mutation.


What's the impact?

This is the first study to use brain imaging techniques to examine the effects of a COMT mutation on cortical thickness and surface area in ADHD vs. typically developing youth. Taken together, the results suggest that abnormal development and maturation of the frontal cortex — as in the case of individuals carrying a COMT mutation — may account for some of the differences in working memory observed between children with and without ADHD. More broadly, these findings present an improvement in understanding how gene function and brain structure interact in neurodevelopmental disorders.  


Jung et al. The Effects of COMT Polymorphism on Cortical Thickness and Surface Area Abnormalities in Children with ADHD. Cerebral Cortex (2018). Access the original scientific publication here.