Phenotypic and genetic characterization of individuals with schizophrenia and high psychiatric hospitalization burden

Disease-course trajectories between individuals with schizophrenia can vary widely. Using longitudinal medical registry data, we constructed a disease severity metric based on the yearly need for psychiatric hospitalizations that tracks past disease-severity for individuals with psychotic disorders. Here, in a large psychosis cohort, we phenotypically and genetically characterized individuals with schizophrenia with the highest need for psychiatric hospital care. The SUPER-Finland study includes 10,403 individuals with a psychotic disorder (schizophrenia, n=5479) and available genotyping data (n=9,892). At recruitment, extensive interview data was collected, including cognitive assessments. Combining the rich interview information with the Finnish medical health care registers, which are nation-wide and have decades of follow-up, we characterized the life-courses of the individuals with schizophrenia who, after psychotic illness onset, had the highest need for psychiatric hospital care (top 20%). Individuals with schizophrenia and the highest need for psychiatric hospitalization, had a substantially lower polygenic score for educational attainment (EA-PGS) (OR=0.81, [0.76-0.86], p=1.51e-10) and a higher PGS for cannabis use disorder (OR=1.15 [1.08-1.23], p=2.57e-05). This group also associated with having received a diagnosis of substance use disorder (SUD) (OR=2.43 [2.12−2.78], p=7.49e−37) and diagnoses related to both adult and childhood behaviour and/or personality problems (p=7.79e−44 and p=1.05e−09). Notably, all these endpoints associated with a low EA-PGS (especially SUD, p= 6.47e-36), but were uncorrelated with the PGS for schizophrenia (SZ-PGS). Having received additional major psychotic diagnoses (i.e schizoaffective disorder, bipolar disorder (BD), and/or psychotic depression) was associated with high BD-PGS (OR=1.17 [1.10-1.24] p=1.30e-07) and were more common in the group with the highest hospitalization burden (OR=1.36 [1.19−1.56], p=9.82e−06). Focusing on the early life-course revealed that the group with the highest hospitalization burden also had an earlier psychotic illness onset (beta= -0.37, p=7.89e-38), and more often needed psychiatric hospital care prior to a first psychotic episode (OR=2.21 [1.92-2.54], p=8.54e-29). Further, they had more often repeated a school year (OR=1.43 [1.17-1.42], p=5.12e-04), had a lower educational level (beta= -0.42, p=6.73e-22), reported more alcohol problems in the family (p=1.85e-04) and separated parents (p=3.27e-07). These early-stage endpoints were primarily associated with the EA-PGS and the SUD-endpoint, with the exception of early age of psychotic onset that had the strongest association with high SZ-PGS (beta= -0.07, p=1.82e-09). In contrast to the EA-PGS and SUD-endpoint, SZ-PGS also associated strongly with treatment resistance (clozapine-use) (p=2.38e-04) and lower average rated function at hospital discharge (p=3.22e-04), two endpoints highly associated with the group needing the most hospital care (p=3.90e-29 and p=1.30e-38, respectively). Our results suggest that a high need of psychiatric hospital care is influenced by low EA-PGS, which in turn was associated with adverse life events. Independently, a high need of psychiatric hospital care was influenced by early psychotic onset, treatment resistance and poor function at discharge, which was primarily associated with high SZ-PGS.