Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders

Lusi Zhang, Scot Kristian Hill, Bin Guo, Baolin Wu, Ney Alliey-Rodriguez, Seenae Eum, Paulo Lizano, Elena I. Ivleva, James L. Reilly, Richard S.E. Keefe, Sarah K. Keedy, Carol A. Tamminga, Godfrey D. Pearlson, Brett A. Clementz, Matcheri S. Keshavan, Elliot S. Gershon, John A. Sweeney, Jeffrey R. Bishop

Research output: Contribution to journalArticlepeer-review

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 (PRS CAD) were quantified for each participant across 13 p-value thresholds (P T 0.5-5e -8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRS CAD was examined in relation to the BACS and the optimized P T was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRS CAD-cognition associations. Multiple regression analyses examined PRS CAD under the optimal P T and medication burden in relation to the BACS composite and subtest scores.

RESULTS: Higher PRS CAD 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 PRS CAD. After controlling for PRS CAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029).

CONCLUSIONS: Higher PRS CAD 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.

Original languageEnglish (US)
Article number110464
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume113
DOIs
StatePublished - Mar 8 2022

Bibliographical note

Funding Information:
This work was supported in part by the National Institute of Mental Health (NIMH) grants MH-083888 (to J.R.B.), MH-072767 (to S.K.H.), MH-078113 (to M.S.K.), MH-077945 (to G.D.P.), MH-083126 (to J.L.R.), MH-077862 (to J.A.S), MH- 103366 (to B.A.C), MH-077851 (to C.A.T.), MH-103368(to E.S.G. and S.K.K.), MH-077852 (to G.K.T.); the American College of Clinical Pharmacy (ACCP) Foundation Futures Grant (to L.Z.). Portions of this work were presented at the 2020 American College of Clinical Pharmacy (ACCP) Virtual Annual Meeting. The funding agencies had no role in the design and conduct of the study collection, management, analysis, and interpretation of the data, and preparation, review, or approval of the manuscript.

Funding Information:
This work was supported in part by the National Institute of Mental Health (NIMH) grants MH-083888 (to J.R.B.), MH-072767 (to S.K.H.), MH-078113 (to M.S.K.), MH-077945 (to G.D.P.), MH-083126 (to J.L.R.), MH-077862 (to J.A.S), MH- 103366 (to B.A.C), MH-077851 (to C.A.T.), MH-103368(to E.S.G. and S.K.K.), MH-077852 (to G.K.T.); the American College of Clinical Pharmacy (ACCP) Foundation Futures Grant (to L.Z.). Portions of this work were presented at the 2020 American College of Clinical Pharmacy (ACCP) Virtual Annual Meeting. The funding agencies had no role in the design and conduct of the study collection, management, analysis, and interpretation of the data, and preparation, review, or approval of the manuscript.J.L.R. has received investigator-initiated support from Naurex, Inc. R.S.E.K. is the owner of VeraSci, a for-profit business that receives revenues from over 100 companies, most of which are pharmaceutical companies. VeraSci holds the copyright for the BACS used in this study, and R.S.E.K receives royalties directly. He has also received consulting income from Akili in the past year. C.A.T. declares an ad hoc consulting relationship with Sunovion, Astellas and Merck and membership on a Merck DSMB; C.A.T. is on the Clinical Advisory Board at Kynexis and Karuna Therapeutics and holds stock in Karuna. M.S.K. has received support from Sunovion and is a consultant to Forum Pharmaceuticals. J.A.S. has received support from VeraSci. The other authors report no related competing interests.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • Cardiovascular medication
  • Cognition
  • Coronary artery disease
  • Polygenic risk score
  • Psychosis

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