Genetic signatures of bipolar disorder course specifiers

BackgroundBipolar disorder (BD) factor models offer limited dimensional understanding due to incomplete integration of psychosocial deficits, long-term outcomes, and transdiagnostic genetics, thus restricting personalised interventions. This study aimed to provide a holistic understanding of BD psychopathology, overcoming this limitation. MethodsExploratory Factor Analysis of 77 OPCRIT items revealed four psychopathological dimensions, and Confirmatory Factor Analysis validated a 20-item, four-factor BD model. Polygenic Risk Scores for five relevant disorders were calculated, and Structural Equation Modelling analysed the genetic contributions to this dimensional model. The study applied Inverse Probability Weighting to address biases in a sample of 4992 participants. ResultsConfirmatory Factor Analysis revealed a novel Adverse Psychosocial Trajectory (APT) dimension, characterised by the co-occurrence of premorbid deficits and poorer long-term outcomes in individuals with BD. Structural Equation Modelling further showed distinct patterns of genetic liability: BD PRS for mania, Schizophrenia (SCZ) PRS for psychosis, and Major Depressive Disorder (MDD) PRS for depression. Notably, the APT dimension exhibited a positive association with Attention-Deficit/Hyperactivity Disorder (ADHD) and anxiety PRSs, and an inverse relationship with BD PRS. ConclusionsThis study offers a novel and clinically relevant dimensional model of BD by identifying the APT dimension, which uniquely integrates crucial premorbid psychosocial factors and outcomes. The identified direct genetic link between ADHD and anxiety with APT (a trajectory associated with poorer BD outcomes) provides important new insight into a challenging illness course. This potentially enables earlier identification and facilitates targeted interventions to improve long-term psychosocial outcomes and overall quality of life in BD.