Genetic Variation in Catechol-O-Methyltransferase

Effects on Working Memory in Schizophrenic Patients, Their Siblings, and Healthy Controls

Catherine M. Diaz-Asper, Terry E. Goldberg, Bhaskar S. Kolachana, Richard E. Straub, Michael F. Egan, Daniel Weinberger

Research output: Contribution to journalArticle

Abstract

Background: Catechol-O-methyltransferase (COMT) val108/158met (rs4680) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865, rs165599, and rs2097603. In a large sample, we examined whether these SNPs affect WM. Methods: Schizophrenic probands (n = 325), their nonpsychotic siblings (n = 359), and normal control subjects (n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Results: Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val108/158met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val108/158met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling. Conclusions: We extended earlier findings of a val108/158met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val108/158met effect in a nonlinear manner.

Original languageEnglish (US)
Pages (from-to)72-79
Number of pages8
JournalBiological Psychiatry
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

Fingerprint

Catechol O-Methyltransferase
Short-Term Memory
Siblings
Single Nucleotide Polymorphism
Homozygote
Dopamine
Schizophrenia
Haplotypes
Analysis of Variance
Alleles
Genes

Keywords

  • Attention
  • catechol-O-methyltransferase
  • COMT
  • prefrontal cognition
  • schizophrenia
  • working memory

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Genetic Variation in Catechol-O-Methyltransferase : Effects on Working Memory in Schizophrenic Patients, Their Siblings, and Healthy Controls. / Diaz-Asper, Catherine M.; Goldberg, Terry E.; Kolachana, Bhaskar S.; Straub, Richard E.; Egan, Michael F.; Weinberger, Daniel.

In: Biological Psychiatry, Vol. 63, No. 1, 01.01.2008, p. 72-79.

Research output: Contribution to journalArticle

Diaz-Asper, Catherine M. ; Goldberg, Terry E. ; Kolachana, Bhaskar S. ; Straub, Richard E. ; Egan, Michael F. ; Weinberger, Daniel. / Genetic Variation in Catechol-O-Methyltransferase : Effects on Working Memory in Schizophrenic Patients, Their Siblings, and Healthy Controls. In: Biological Psychiatry. 2008 ; Vol. 63, No. 1. pp. 72-79.
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AB - Background: Catechol-O-methyltransferase (COMT) val108/158met (rs4680) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865, rs165599, and rs2097603. In a large sample, we examined whether these SNPs affect WM. Methods: Schizophrenic probands (n = 325), their nonpsychotic siblings (n = 359), and normal control subjects (n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Results: Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val108/158met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val108/158met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling. Conclusions: We extended earlier findings of a val108/158met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val108/158met effect in a nonlinear manner.

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