Polygenic Risk Scores for Pediatric Obsessive-Compulsive Symptoms and their Mediating Effect in Clinically Diagnosed Samples of Obsessive-Compulsive Disorder, Attention-Deficit/Hyperactivity Disorder, Anxiety, Depression, Autism and Tic Disorders
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Here, we present the first genome-wide association study and polygenic risk score analysis of obsessive-compulsive symptoms in a sample of 661 clinically diagnosed pediatric participants diagnosed with mental illness and healthy controls. Using a psychiatric questionnaire score as a quantitative trait we conducted a large-scale genetic analysis and ran multiple post-association analyses to investigate the mediating role of obsessive-compulsive symptoms in six comorbid mental disorders. Polygenic risk scores were computed for OCS using genome-wide summary statistics from obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, anxiety disorders, depression, autism spectrum disorder, and tic disorders. Across all models, the PRS of OCS explained approximately 1-2% of the variance in six mental disorders. Furthermore, Mendelian randomization analysis suggested a potential causal pathway in which OCS mediates the genetic risk for anxiety. These findings highlight shared polygenic mechanisms between OCS and a range of neuropsychiatric conditions. We observed a potential causal pathway in which OCS mediates the genetic risk for anxiety, supporting the hypothesis that OCS may serve as a transdiagnostic mediator within the pediatric population. This study underscores the value of examining genetic risk across the symptom spectrum of mental illnesses, rather than relying solely on binary diagnostic categories.
