Polygenic Scores for Schizophrenia and Educational Attainment Predict Global Functioning Across Psychiatric Hospitalization Among People with Schizophrenia

Key PointsO_ST_ABSQuestionC_ST_ABSIs variation in global functioning among people with schizophrenia associated with genetic differences? FindingsIn this genetic association study of 5991 adults with schizophrenia and 59,795 hospitalizations, polygenic scores for schizophrenia and educational attainment predicted global functioning at psychiatric admission and discharge, as well as the magnitude of functional improvement during hospitalization. Higher polygenic burden for schizophrenia was consistently associated with worse functional outcomes, including less functional improvement during hospitalization, while educational attainment polygenic score showed a more complex pattern of associations. MeaningPolygenic scores may help disentangle heterogeneity in schizophrenia functioning and course. ImportanceSchizophrenia is characterized by heterogeneity in disease outcomes and course. The extent to which this heterogeneity is associated with genetic variation is unclear. ObjectiveTo investigate whether polygenic scores (PGS) for schizophrenia and educational attainment are associated with global functioning during inpatient psychiatric hospitalization among patients with schizophrenia. Design, Setting, and ParticipantsAdults with schizophrenia were recruited nationwide for the SUPER-Finland Study between 2015 and 2018. Global functioning scores recorded during hospitalizations between 1994 and 2019 were extracted from a complete, longitudinal register. Data for the current genetic association study were analyzed between May 2024 and April 2025. We used linear mixed-effects models to examine associations among PGS and global functioning at admission and discharge, as well as functional change during hospitalization. ExposuresPsychiatric hospitalization and PGS for schizophrenia and educational attainment. Main Outcomes and MeasuresAdmission global functioning, discharge global functioning, and functional change during hospitalization. ResultsWe analyzed 117,810 global functioning scores from 59,795 hospitalizations and 5991 participants (2733 [45.62%] female, median [IQR] age = 47 [20] years). Higher schizophrenia PGS predicted lower admission global functioning ({beta} = -0.20; 95% CI, -0.40 to 0.00; P = .05) and discharge global functioning ({beta} = -0.36; 95% CI,-0.56 to -0.17; P < .001), and less functional improvement ({beta} = -0.31; 95% CI, -0.49 to -0.14; P < .001). Higher educational attainment PGS predicted greater functional improvement ({beta} = 0.20; 95% CI, 0.03 to 0.37; P = .02) but worse admission global functioning ({beta} = -0.23; 95% CI, -0.43 to -0.04; P = .02). Conclusions and RelevanceHigher genetic liability for schizophrenia is associated with worse global functioning across psychiatric hospitalization, including less functional improvement. Integrating PGS and clinically relevant, longitudinal disease outcomes may help parse heterogeneity in schizophrenia prognosis and course.