Imaging Shows At-Risk Genetics May Impact Kids’ Cognition

Cortical development may be a mediator between COMT genotype and cognitive performance in children, and may also be a mediator for the onset of schizophrenia and psychosis, a researcher reported.

In a study of 88 children (ages 1-16 years) that used brain MRI and catechol-O-methyltransferase (COMT) genotyping, as well as learning composite scores, COMT genotype to non-verbal Development Quotient (NVDQ) relationships were mediated by cortical thickness in the pericalcarine cortex, supramarginal gyrus, and transverse temporal gyrus, according to Justin Remer, MD, of the University of California San Francisco.

Also, COMT genotype to Verbal Development Quotient (VDQ) relationships were mediated by cortical development in the pericalcarine cortex, isthmus of the cingulate, and caudal middle frontal gyrus, Remer reported at the Radiological Society of North America virtual meeting.

Finally, COMT genotype to Early Learning Composite (ELC) relationships were mediated by cortical development in the entorhinal cortex, cuneus, and fusiform gyrus. ELC is a surrogate measure of IQ, according to Remer and colleagues.

“The results show that the longitudinal cognitive developmental differences in children based on [COMT genotype] can be explained by differences in cortical thickness development,” they wrote.

“The children in the study had no symptoms of psychiatric disorders, and were considered typically developing,” according to Remer, and the finding indicated that brain differences in children with at-risk genetics are tied to differences in cognitive performance. COMT is a critical enzyme involved in frontal and temporal lobe dopamine metabolism. The rs4680 Valine108/158:Methionine polymorphism has been shown through convergent functional genomics to be one significant genetic variant correlated with an increased risk of schizophrenia.

This is the first study to explore the role of cortical development as a mediator between COMT genotype and cognitive performance, and possibly as a mediator for onset of schizophrenia and psychosis, according to Remer.

“MRI in children with abnormal COMT genetics offers insight into neuroanatomical differences that manifest before clinical symptoms, and might represent a window of opportunity for intervention,” he said. “The most exciting finding…was that differences in development in specific neuroanatomical locations, such as the cuneus and entorhinal cortex based on a child’s COMT genotype, can explain differences in early learning composite, a measure of overall cognitive performance.”

Yang Wang, MD, PhD, of the Medical College of Wisconsin in Milwaukee, told MedPage Today that the study was “very interesting, as it is the first imaging study to demonstrate effects of COMT variants on cortical thickness development in very young children.”

However, Wang, who was not involved in the study, noted that “It would be more informative if this study could be replicated at a large scale to detect such effects at different age groups during normal development. More research work is warranted to evaluate clinical implications of such findings.”

He also stated that COMT catalyzes the degradation of catecholamines and the methylation of catechol estrogens. “Due to its role in dopamine degradation, the COMT gene has received attention as a genetic contributor to variations in cognitive function,” he said.

Remer noted that currently no therapy exists to alter an an individual’s COMT genotype. “We hope the findings of imaging studies will serve as a foundation for understanding anatomical differences associated with differential genetics,” he said. “By exploring microstructural changes on imaging, and correlating these changes with cognitive performance in individuals before onset of any neurologic or psychiatric disease, we hope to understand potential subtle deviations in early development that can provide further insight onto the complex role of the COMT genotype.”

He stressed that “schizophrenia is a major and debilitating psychiatric condition with a poorly understood etiology…We hope that our results not only further demonstrate the importance in studying brain development prior to disease onset, but also that the differences in brain anatomy play an important role in explaining differences in pediatric cognitive performance.”

Remer explained to MedPage Today that the COMT genotype test is a polymerase chain reaction (PCR) test from buccal mucosa cells. “Right now, the test is only performed for research purposes, and there is not a current clinical indication for COMT genotype screening,” he said. “Nevertheless, understanding differential genetics in people with altered neurotransmitter metabolism is important research and, hopefully, as we and other groups continue to study this gene and its effects on brain development, we will further elucidate the role of using this gene for clinical practice.”