Family-level Brain Pattern Similarities and Their Clinical Significance in Young Offspring of Individuals with Psychotic Disorders.

OBJECTIVE: Familial high-risk offspring inherently provide an unparalleled opportunity for individual-level risk prediction in psychotic disorders: a personalized forecast of their potential brain pathology should they develop psychosis, i.e. their own parents' brain pathology. However, whether brain patterns in offspring resembling those of their affected parents have clinical significance remains unclear. This study aims to quantify these parent-offspring brain similarities in psychotic disorders and explore their clinical significance. METHODS: Using 3T imaging data from the Bipolar Schizophrenia Network on Intermediate Phenotypes (BSNIP)-1 Study, cortical thickness similarities between offspring (ages 15-35, N=73) and their own affected parents with psychosis were quantified using a novel Familial Vulnerability Index (FVI), calculated using region-wise z-scores. FVIs were compared to the ENIGMA-derived cortical Regional Vulnerability Index (RVI) in offspring. FVIs and RVIs were examined in offspring with and without psychiatric symptoms, and relations to global and cognitive functioning were assessed. RESULTS: Offspring had higher FVIs than RVIs (q<0.001, d=0.78). Offspring with a psychotic disorder (q=0.001, d=2.84) or any other psychiatric diagnosis (q=0.02, d=1.40) had higher FVIs than offspring with no psychiatric diagnosis, while RVIs did not differ between these groups. FVIs, not RVIs, were negatively correlated with global functioning (r =-0.31, q=0.047). Neither FVIs nor RVIs were correlated with cognition. CONCLUSION: This proof-of-concept study demonstrates the clinical significance of FVI in young offspring of individuals with psychotic disorders. Future research on the clinical utility of family-level similarities across modalities holds untapped potential to advance risk and prognostic prediction in families affected by serious mental illness.