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Relationship to Catechol-O-methyltransferase Val158Met Genotype and Schizophrenia

Terry E. Goldberg, PhD; Michael F. Egan, MD; Tonya Gscheidle, BA; Richard Coppola, PhD; Thomas Weickert, PhD; Bhaskar S. Kolachana, PhD; David Goldman, MD; Daniel R. Weinberger, MD

Arch Gen Psychiatry. 2003;60:889-896.

Background  Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia.

Methods  Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol-O-methyltransferase (COMT) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling.

Results  A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions.

Conclusions  A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition.

From the Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health (Drs Goldberg, Egan, Coppola, Weickert, Kolachana, and Weinberger and Ms Gscheidle), and the Laboratory of Neurogenetics, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (Dr Goldman), Bethesda, Md. Drs Goldberg, Egan, Kolachana, Goldman, and Weinberger have a patent pending for use of COMT Val/Met to develop treatments for working memory impairments.

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