Polygenic risk scores for pediatric obsessive-compulsive symptoms: Mediating effects in samples clinically diagnosed with mental disorders

Here, we present the first genome-wide association study of obsessive-compulsive symptoms in a sample of clinically diagnosed pediatric participants 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 neuropsychiatric disorders. Although no SNPs reached genome-wide significance, we identified suggestive associations on chromosomes 4, 5, 6, 7, 9, 17, 19, and 22. Notable genes mapped to these regions were highlighted, though none met the threshold for multiple testing correction. Further, polygenic risk scoring and Mendelian randomization analyses explored the potential mediating role and genetic disposition of obsessive-compulsive symptoms in obsessive-compulsive disorder, anxiety, attention-deficit/hyperactivity disorder, depression, autism spectrum disorders and/or Tourette syndrome. We found that genetic predisposition for OCS accounts for approximately 2% in individuals with one or more of these six disorders, with a particularly strong mediation effect observed for anxiety disorders. This study underscores the value of examining genetic risk across the symptom spectrum of mental illnesses, rather than relying solely on binary diagnostic categories.