Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis

Abstract

Background Similar smooth pursuit eye tracking dysfunctions are present across psychotic disorders. They include pursuit initiation and maintenance deficits that implicate different functional brain systems. This candidate gene study examined psychosis-related genotypes regulating dopamine and glutamate neurotransmission in relation to these pursuit deficits. Methods 138 untreated first-episode patients with a psychotic disorder were genotyped for four markers in DRD2 and four markers in GRM3. The magnitude of eye movement abnormality in patients was defined in relation to performance of matched healthy controls (N=130). 83 patients were followed after 6 weeks of antipsychotic treatment. Results At baseline, patients with a -141C deletion in DRD2 rs1799732 had slower initiation eye velocity and longer pursuit latency than CC insertion carriers. Further, GRM3 rs274622_CC carriers had poorer pursuit maintenance than T-carriers. Antipsychotic treatment resulted in prolonged pursuit latency in DRD2 rs1799732_CC insertion carriers and a decline in pursuit maintenance in GRM3 rs6465084_GG carriers. Conclusions The present study demonstrates for the first time that neurophysiological measures of motor and neurocognitive deficits in patients with psychotic disorders have different associations with genes regulating dopamine and glutamate systems respectively. Alterations of striatal D2 receptor activity through the -141C Ins/Del polymorphism could contribute to pursuit initiation deficits in psychotic disorders. Alterations in GRM3 coding for the mGluR3 protein may impair pursuit maintenance by compromising higher perceptual and cognitive processes that depend on optimal glutamate signaling in corticocortical circuits. DRD2 and GRM3 genotypes also selectively modulated the severity of adverse motor and neurocognitive changes resulting from antipsychotic treatment.

Effect of metabotropic glutamate receptor-3 variants on prefrontal brain activity in schizophrenia: An imaging genetics study using multi-channel near-infrared spectroscopy

“…(Corti et al, 2001). In addition, other clinical studies have reported that rs274622_CC carriers showed a poorer performance in the maintenance of pursuit eye movement than did T-carriers (Lencer et al, 2014), and the addicts carrying the C allele of rs274622 had a shortened duration for transition from first use to dependence in comparison to TT carriers (Jia et al, 2014). Taking these previous findings into consideration, we conceived that the C allele could dysregulate glutamate transmission, which may lead to decreased brain activity in schizophrenia.…”

“…Fourth, although the effects of each GRM3 SNP on brain activity in the prefrontal cortex are not fully understood (Bishop et al, 2015;Egan et al, 2004;Lencer et al, 2014;Marenco et al, 2006;Tan et al, 2007a;Xia et al, 2012), we divided participants into two SNP subgroups because of small sample size. Genotype group differences without any grouping may clarify the GRM3 effect on brain function.…”

Evaluation of relationship between GRM3 polymorphisms and cognitive function in schizophrenia of Han Chinese

“…It was reported that genetic variants in the GRM3 gene were associated with schizophrenia-related endophenotypes such as impaired cognition, cortical activation and glutamate markers . Moreover, the association of rs6465084 in GRM3 gene with cognitive processes has been recently reported to drive smooth pursuit eye movements in patients with psychotic disorders, which suggested that alterations in GRM3 coding for the mGluR3 protein may impair pursuit maintenance by compromising higher perceptual and cognitive processes that depend on optimal glutamate signaling in corticocortical circuits (Lencer et al, 2014). These conclusions are consistent with our results, which all provide further supportive evidence that the effects of gene variations on cognitive deficits could be associated with phenotype, despite a mechanistic rationale to explain the association remaining to be investigated.…”

Pursuit eye movements as an intermediate phenotype across psychotic disorders: Evidence from the B-SNIP study

“…Further, we recently demonstrated different associations of sensorimotor and sustained pursuit maintenance impairments with genes regulating dopamine and glutamate systems in psychotic disorders (Lencer et al, 2014). …”