Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls

Abstract

Objective: Cognitive impairment is a core feature of schizophrenia, related to dopaminergic dysfunction in the prefrontal cortex (PFC). It is hypothesized that functional single nucleotide polymorphism (SNP) rs4680 of the catechol-O-methyltransferase (COMT) gene could mediate the relationship between cognition and dopamine activity in the PFC. Other COMT SNPs could also play a role. Methods: We evaluated the role of three COMT SNPs (rs737865, rs165599, and rs4680) in schizophrenia and their impact on three working memory tasks. For genetic association analyses, 212 individuals with schizophrenia and 257 healthy controls (HCs) were selected. The Visual Working Memory (VWM) Task, Keep Track Task, and Letter Memory Task were administered to 133 schizophrenics and 93 HCs. Results: We found a significant association of rs737865, with the GG genotype exerting a protective effect and the GA haplotype (rs4680/rs165599) exerting a risk effect for schizophrenia. COMT rs4680 AA carriers and rs737865 AA carriers scored lowest on the Keep Track Task. When the genotype*group interaction effect was evaluated, rs165599 exerted opposite effects for VWM and Keep Track task performance in patients and controls, with AA carriers scoring lowest on both tests among controls, but highest among patients. Conclusion: These data support the hypothesis that COMT polymorphisms may be associated with schizophrenia and modulate cognition in patients and controls.

Effects of COMT Genotypes on Working Memory Performance in Fibromyalgia Patients

“…Finally, contrary to our expectations, the Met/Met genotype (i.e., that with low enzyme activity) was not associated with an improvement in working memory tasks in fibromyalgia. Although there is a lack of previous studies linking these genetic factors with cognitive dysfunction in fibromyalgia, the relationship between the COMT rs4680 polymorphism and working memory functioning has been consistently reported in healthy volunteers [28,30,31,34,94] and other pathologies characterized by working memory impairments such as schizophrenia or posttraumatic stress disorder [36][37][38][39]. It has been demonstrated that Val/Val carriers scored systematically lower than individuals carrying other genotypes on various working memory tasks.…”

“…These data also seem to have a neurophysiological correlate, since brain imaging studies have shown that Val carriers exhibited a decrease in dopamine levels within the PFC, reducing the blood-oxygen-level dependent (BOLD) response of this brain region compared to that in the Met carriers [31,36], and also reflected by the poor performance of Val carriers in working memory tests [29]. These results have also been replicated in chronic patients, such as those suffering from posttraumatic stress disorder or schizophrenia [36][37][38][39], leading to the consideration of this gene as a therapeutic target for improving cognitive symptoms [40].…”

Effects of working memory training on emotion regulation: Transdiagnostic review

“…However, more stable factors, such as genetics, have also been implicated in working memory performance (Wang, Deater‐Deckard, Cutting, Thompson, & Petrill, ; Zhou et al, ). Association studies have implicated genetic polymorphisms related to dopamine or glutamatergic transmission to working memory (Matsuzaka et al, ; Okochi et al, ; Poletti et al, ).…”

Association between COMT gene rs165599 SNP and schizophrenia: A meta‐analysis of case‐control studies

“…Gupta et al (), in their study of the Indians, reported an association with disease in a different sequence of haplotype block studied by Shifman et al () and also in the haplotype block with seven SNPs in which other SNPs were also included. In the study of Matsuzaka, Christofolini, and Ota (), it is stated that by haplotype analysis of rs4680‐rs165599, an association between G‐A haplotype and schizophrenia was obtained when compared with G‐G haplotype.…”