COMT and GAD1 gene polymorphisms are associated with impaired antisaccade task performance in schizophrenic patients

Abstract

Genetic influences modulating executive functions engaging prefrontal cortical brain systems were investigated in 141 male subjects. The effects of variations in two genes implicated in dopamine and GABA activities in the prefrontal cortex: rs4680 (Val158/Met polymorphism of the catechol-o-methyltransferase gene-COMT) and rs3749034 (C/T) substitution in the promoter region of the glutamic acid decarboxylase gene (GAD1) were studied on antisaccade (AS) performance in healthy subjects and schizophrenic patients. Genotyping revealed a trend towards a reduced proportion of COMT Val/Met heterozygotes and a significantly increased frequency of the GAD1 rs3749034 C allele in schizophrenic patients relative to controls. Patients had elevated error rates, increased AS latencies and increased latency variability (coefficient of variation) compared to controls. The influence of polymorphisms was observed only in patients but not in controls. A substantial effect of the COMT genotype was noted on the coefficient of variation in latency, and this measure was higher in Val homozygotes compared to Met allele carriers (p < 0.05) in the patient group. The outcome from rs3749034 was also disclosed on the error rate (higher in T carriers relative to C homozygotes, p < 0.01) and latency (increased in C homozygotes relative to T carriers, p < 0.01). Binary logistic regression showed that inclusion of the genotype factor (i.e., selective estimation of antisaccade measures in CC carriers) considerably increased the validity of the diagnostic model based on the AS measures. These findings may well be derived from specific genetic associations with prefrontal cortex functioning in schizophrenia.

Keywords: Antisaccade task; COMT rs4680 polymorphism; GAD1 rs3749034 polymorphism; Schizophrenia.

Fig. 1

Antisaccade experimental paradigm and examples of Electrooculogram (EOG) recording. a Experimental design of the visual stimuli presentation (dark circle—stimulus switched “on”; light circle—stimulus switched “off”). b Example of EOG recording

Fig. 2

The effects of COMT Val158Met polymorphism on antisaccade parameters in schizophrenic patients (Sch) and healthy controls (Con). a Antisaccade error rate (%), **p < 0.01 relative to the carriers of the same COMT genotype from the Con group. b Antisaccade latency (ms), *p < 0.05 relative to the carriers of the same COMT genotype from the Con group. c Coefficient of variation of antisaccade latency, (%). **p < 0.01 relative to the carriers of the Val/Val COMT genotype from the Con group, ^## p < 0.01 relative to Val/Met carriers from the Sch group, ^{^} p < 0.05 relative to Met/Met carriers from Sch group

Fig. 3

The effects of rs3749034 polymorphism of GAD1 on antisaccade parameters in schizophrenic patients (Sch) and healthy controls (Con). a Error rate, %. *p < 0.05, **p < 0.01 relative to the carriers of the same genotype from the Con group, ^# p < 0.05 relative to the carriers of the C/C genotype from Sch group, b Latency, ms. **p < 0.01 relative to the cariers of C/C genotype from Con group, ^# p < 0.05 relative to the carriers of C/C genotype from Sch group. c Coefficient of variation of antisaccade latency, %. *p < 0.05, **p < 0.01 relative to the carriers of the same genotype from the Con group

Fig. 4

Scheme summarizing the principal findings