Multi-polygenic scores in psychiatry: from disorder-specific to transdiagnostic perspectives

The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. In a deeply-phenotyped sample (n=513) consisting of 452 patients from tertiary care with mood disorders, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and/or substance use disorders (SUD) and 61 unaffected comparison individuals, we derived subject-specific multi-base polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions. High PRS for depression was unselectively associated with the diagnosis of SUD, ADHD, anxiety disorders, mood disorders, and the comorbidities among them. In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems but not others. This study highlights a misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology, and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.