Polygenic Scores for Schizophrenia and Educational Attainment Predict Global Functioning Across Psychiatric Hospitalization Among People with Schizophrenia
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This genetic association study analyzed 5991 adults with schizophrenia and 59,795 psychiatric hospitalizations in the SUPER-Finland cohort, using linear mixed-effects models to test whether polygenic scores (PGS) for schizophrenia and educational attainment predicted global functioning at admission and discharge and the degree of functional improvement during hospitalization. Higher schizophrenia PGS was consistently associated with lower global functioning at admission and discharge and with less functional improvement over time, while educational attainment PGS showed a more complex pattern, including greater functional improvement but worse admission global functioning. A key limitation explicitly reflected by the design is that the paper uses observational longitudinal register data and reports modest associations for schizophrenia PGS at admission (borderline statistical evidence). This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
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Abstract
Key Points Question Is variation in global functioning among people with schizophrenia associated with genetic differences? Findings In 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. Meaning Polygenic scores may help disentangle heterogeneity in schizophrenia functioning and course. Importance Schizophrenia is characterized by heterogeneity in disease outcomes and course. The extent to which this heterogeneity is associated with genetic variation is unclear. Objective To 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 Participants Adults 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. Exposures Psychiatric hospitalization and PGS for schizophrenia and educational attainment. Main Outcomes and Measures Admission global functioning, discharge global functioning, and functional change during hospitalization. Results We 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 ( β = −0.20; 95% CI, −0.40 to 0.00; P = .05) and discharge global functioning ( β = −0.36; 95% CI,−0.56 to −0.17; P < .001), and less functional improvement ( β = −0.31; 95% CI, −0.49 to −0.14; P < .001). Higher educational attainment PGS predicted greater functional improvement ( β = 0.20; 95% CI, 0.03 to 0.37; P = .02) but worse admission global functioning ( β = −0.23; 95% CI, −0.43 to −0.04; P = .02). Conclusions and Relevance Higher 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.
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Abstract
Question Is variation in global functioning among people with schizophrenia associated with genetic differences?
Findings In 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.
Meaning Polygenic scores may help disentangle heterogeneity in schizophrenia functioning and course.
Importance Schizophrenia is characterized by heterogeneity in disease outcomes and course. The extent to which this heterogeneity is associated with genetic variation is unclear.
Objective
To 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 Participants Adults 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.
Exposures Psychiatric hospitalization and PGS for schizophrenia and educational attainment.
Main Outcomes and Measures Admission global functioning, discharge global functioning, and functional change during hospitalization.
Results
We 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 (β = −0.20; 95% CI, −0.40 to 0.00; P = .05) and discharge global functioning (β = −0.36; 95% CI,−0.56 to −0.17; P < .001), and less functional improvement (β = −0.31; 95% CI, −0.49 to −0.14; P < .001). Higher educational attainment PGS predicted greater functional improvement (β = 0.20; 95% CI, 0.03 to 0.37; P = .02) but worse admission global functioning (β = −0.23; 95% CI, −0.43 to −0.04; P = .02).
Conclusions
and Relevance Higher 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.
Competing Interest Statement
Dr. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with options), and has received grant support from Biogen, Inc. Dr. Neale is a member of the scientific advisory board at Deep Genomics.
Funding Statement
This work was supported by the Stanley Family Foundation and by National Institute of Mental Health grant R37MH107649. Dr. Giangrande is supported by the Pamela Sklar Psychiatric Genetics and Neuroscience Fellowship. Dr. Kämpe is supported by the Swedish Society for Medical Research (grant: PD20-0190).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committee of the Hospital District of Helsinki and Uusimaa gave ethical approval for this work.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data Availability
Deidentified data from the SUPER-Finland cohort is available upon reasonable request to Drs. Palotie and Pietiläinen. Data for SUPER-Finland participants who provided consent for biobank participation are available from the THL Biobank (https://thl.fi/en/research-and-development/thl-biobank/for-researchers/sample-collections/super-study). Researchers may apply for access to register data from the Finnish Social and Health Data Permit Authority (Findata; https://findata.fi/en/). Code used to perform analyses and generate figures is available at https://github.com/egiangrande/SUPER_GlobalFunctioning_SZ.
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