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

Meta-analysis supports GWAS-implicated link between GRM3 and schizophrenia risk

“… 1 Among these associations, the metabotropic glutamate receptor 3 ( GRM3 ) contained the second most significant single-nucleotide polymorphism (SNP) (rs12704290, P =3.33 × 10 −10 ). 1 This PGC finding complements a number of previous associations between GRM3 and schizophrenia-related phenotypes, such as prefrontal activation during cognitive tasks, 2 white matter integrity, 3 hippocampal volume in severe obstetric complications, 4 poor cognitive performance (that is, verbal fluency, digit symbol test, perseverative error processing and spatial working memory), 5 , 6 , 7 , 8 , 9 antipsychotic response in first-episode schizophrenia 10 and positive symptoms severity in treatment-resistant schizophrenia. 5 However, two meta-analyses of GRM3 SNPs have failed to support an association with schizophrenia risk.…”

“…Since the publication of the most recent GRM3 meta-analysis, 12 there have been three additional studies published involving 6027 (2381 schizophrenia and 3646 control) individuals, 2 , 6 , 13 indicating a reappraisal is warranted. Thus, the aim of this study was to provide an updated and more comprehensive meta-analysis of the association between GRM3 genetic variation and schizophrenia by including both case–control and family studies as well as an exploration of potential population stratification.…”

mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions

“…Indeed, genetic variations in GRM3, but not GRM2, are associated with schizophrenia, and with altered dlPFC activation and lower performance during cognitive tasks. 9,11,18 Studies using knockout animals also suggest that mGluR3 depletion leads to working memory impairments in mice. 67,68 Interestingly, methylation of the promoter region of GRM2, which reduces mGluR2 expression, lowers the risk of schizophrenia.…”

“…1,2 Although initial trials with mGluR2/3 agonists have had mixed results, [3][4][5][6][7] data increasingly indicate that changes in mGluR3 are associated with schizophrenia and aging, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] encouraging this treatment strategy. Clinical trials were originally based on data from rodent models.…”

“…45,46 Insults to disrupted in schizophrenia 1 and phosphodiesterase 4A are linked to increased risk of illness. 47,48 Importantly, genetic alterations in mGluR3 are increasingly linked to schizophrenia, [8][9][10][11][12][13][14][15][16][17][18][19][20][21] including altered dlPFC activation and poorer cognitive performance. 9,11 In particular, there is reduced mGluR3 protein in schizophrenia dlPFC, and an increase in GCPII, the enzyme that catabolizes the endogenous mGluR3 ligand, NAAG.…”