Association of Brain Structural Measurements and Polygenic Risk Scores with Obsessive-Compulsive Symptoms in Adolescents Diagnosed with Obsessive-Compulsive Disorder, Attention-Deficit/Hyperactivity Disorder, Anxiety, Depression, Autism and Tic Disorders

Obsessive-compulsive symptoms, characterized by intrusive thoughts and repetitive behaviors, are prevalent among youth. These symptoms are known to be moderately heritable and linked to structural brain changes involved in their pathophysiology. This study investigates the connections between structural brain alterations (cortical thickness, surface area and subcortical volume), genetic variation, and childhood obsessive-compulsive symptom scores within 143 samples of healthy control participants and cases diagnosed with obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, anxiety disorder, autism spectrum disorders and/or tic disorders. We hypothesize that the effect of genetic variants on standardized scores of obsessive-compulsive symptoms is mediated by imaging endophenotypes. To do so we test for associations between polygenic risk scores and structural imaging phenotypes within cortico-striato-thalamo-cortical circuitry and perform mendelian randomization analyses to identify potential causal pathways linking polygenic risk scores of structural brain alterations and obsessive-compulsive symptoms assessed with the Obsessive-Compulsive Subscale of the Child Behavior Checklist. We observed that changes in cortical thickness of rostral middle frontal cortex and surface area of orbitofrontal cortex, along with other four regions have a significant genetic contribution in obsessive-compulsive symptom severity in adolescent samples. Additionally, surface area of inferior parietal lobule may act as a causal mediator between high-risk variants and obsessive-compulsive symptoms. The mentioned three regions are part of cortico-striato-thalamo-cortical circuitry that have various regulatory effects on obsessive-compulsive symptoms. If these findings replicated in larger samples, they could offer valuable insights into the neurobiology of obsessive-compulsive traits and related structural alterations in specific brain regions.