Brain Anatomical Mediators of GRIN2B Gene Association with Attention/Hyperactivity Problems: An Integrated Genetic-Neuroimaging Study

Abstract

This study aims to investigate the genetic and neural determinants of attention and hyperactivity problems. Using a proof-of-concept imaging genetics mediation design, we explore the relationship between the glutamatergic GRIN2B gene variants and inattention/hyperactivity with neuroanatomical measures as intermediates. Fifty-eight children and adolescents were evaluated for behavioral problems at three time points over approximately 7 years. The final assessment included blood drawing for genetic analyses and 3T magnetic resonance imaging. Attention/hyperactivity problems based on the Child Behavior Checklist/6-18, six GRIN2B polymorphisms and regional cortical thickness, and surface area and volume were estimated. Using general linear model (GLM) and mediation analyses, we tested whether GRIN2B exerted an influence on stable inattention/hyperactivity over development, and to what extent this effect was mediated by brain morphology. GLM results enlightened the relation between GRIN2B rs5796555-/A, volume in the left cingulate isthmus and inferior parietal cortices and inattention/hyperactivity. The mediation results showed that rs5796555-/A effect on inattention/hyperactivity was partially mediated by volume in the left isthmus of the cingulate cortex, suggesting a key role of this region in translating glutamatergic GRIN2B variations to attention/hyperactivity problems. This evidence can have important implications in the management of neurodevelopmental and psychiatric disorders.

Characterizing Sensory Phenotypes of Subgroups with a Known Genetic Etiology Pertaining to Diagnoses of Autism Spectrum Disorder and Intellectual Disability

“…It may be the case that this phenotype is linked to an atypical attention phenotype also proposed given elevated prevalence of ADHD in GRIN2B (Dorval et al, 2007 ). In fact, new evidence implicates a role for one GRIN2B polymorphism (rs5796555-/A) for hyperactivity behaviors that are mediated by the density of the left isthmus of the cingulate cortex (Nobile et al, 2021 ). This region plays an important role in executive functions (Fornito et al, 2004 ) and preliminary evidence suggests cortical thickness may be distinct in autistic individuals (Hau et al, 2019 ).…”

Right frontal cingulate cortex mediates the effect of prenatal complications on youth internalizing behaviors.

“…All subjects underwent two clinical assessments over around ve years (Waves 1 and 2) followed by a follow-up clinical and neuroimaging assessment (Wave 2, after 7.39 ± 1.65 years from Wave 1). Further details on the GENESIS project can be found in (34,52).…”

“…In the present study, we aimed at examining the impact of prenatal and perinatal complications on brain structure and behavioral traits in children and adolescents who took part in the multicentric GENESIS project (52). We also aimed at assessing the possible role of brain structure as mediator in the causal link between early life factors and behavior.…”