Catechol-O-methyltransferase genotype differentially contributes to the flexibility and stability of cognitive sets in patients with psychotic disorders and their first-degree relatives

William C. Hochberger, Courtney L.M. Eskridge, Jeffrey R. Bishop, James L. Reilly, Leah H. Rubin, Sarah Keedy, Elliot S. Gershon, Carol A. Tamminga, Godfrey D. Pearlson, Michael Ragozzino, Matcheri S. Keshavan, John A. Sweeney, S. Kristian Hill

Research output: Contribution to journalArticlepeer-review


Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype.

Original languageEnglish (US)
Pages (from-to)236-241
Number of pages6
JournalSchizophrenia Research
StatePublished - Sep 2020

Bibliographical note

Funding Information:
This study was supported in part by NIMH grants MH078113 , MH077945 , MH077852 , MH077851 , MH077862 , MH072767 , and MH083888 . The writing of this manuscript was also supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs .

Publisher Copyright:
© 2020 Elsevier B.V.

Copyright 2021 Elsevier B.V., All rights reserved.


  • B-SNIP 1
  • Catechol-O-methyltransferase (COMT)
  • Penn conditional exclusion task (PCET)
  • Psychosis
  • Set shifting

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Fingerprint Dive into the research topics of 'Catechol-O-methyltransferase genotype differentially contributes to the flexibility and stability of cognitive sets in patients with psychotic disorders and their first-degree relatives'. Together they form a unique fingerprint.

Cite this