Lusi Zhang1, Scot Kristian Hill2, Bin Guo3, Baolin Wu3, Ney Alliey-Rodriguez4, Seenae Eum5, Paulo Lizano6, Elena I Ivleva7, James L Reilly8, Richard S E Keefe9, Sarah K Keedy4, Carol A Tamminga7, Godfrey D Pearlson10, Brett A Clementz11, Matcheri S Keshavan6, Elliot S Gershon4, John A Sweeney12, Jeffrey R Bishop13. 1. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States of America. 2. Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States of America. 3. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America. 4. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States of America. 5. Department of Pharmacogenomics, School of Pharmacy, Shenandoah University, Fairfax, VA, United States of America. 6. Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America. 7. Department of Psychiatry, Southwestern Medical Center, University of Texas, Dallas, TX, United States of America. 8. Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America. 9. Departments of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States of America. 10. Departments of Psychiatry and Neurobiology, School of Medicine, Yale University, New Haven, CT, United States of America. 11. Department of Psychology and Neuroscience, University of Georgia, Athens, GA, United States of America. 12. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States of America. 13. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States of America; Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, MN, United States of America. Electronic address: jrbishop@umn.edu.
Abstract
BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). CONCLUSIONS: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.
BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). CONCLUSIONS: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.
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