| Dopaminergic activity, measured indirectly through the high (Met) and low (Val) activity polymorphisms of Catechol-O-Methyltransferase (COMT), has been reliably demonstrated to influence cognitive function in psychosis, particularly set shifting. Two important components of set shifting are cognitive flexibility and stability---which can be assessed via error type (perseverative versus regressive) on the Penn Conditional Exclusion Test (PCET). However, no connection has been established between PCET error type and COMT genotype across psychotic disorders or their first-degree relatives. This study examined the relationship between the executive process of set shifting and COMT genotype. Participants were 515 psychosis spectrum probands (schizophrenia, schizoaffective, psychotic bipolar), 584 of their first-degree relatives, and 233 non-psychiatric controls from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Findings indicated that increased rates of perseverative errors (impaired flexibility) were associated the low-activity COMT enzyme (Met/Met allele), and regressive errors (impaired stability) were associated with the high-activity COMT enzyme (any Val allele). Moreover, probands with one or more Val alleles showed elevated rates of regressive errors relative to non-clinical participants (healthy controls, first-degree relatives), making the Val allele of COMT a potential biomarker for deficits in cognitive stability in psychosis. These findings support COMT as a moderator of cognitive flexibility and stability, and the Val allele as a potential biomarker for psychosis. |
