Background: GRM5 is the gene encoding for the metabotropic glutamate receptor type 5 (mGluR5), a postsynaptic G-protein coupled receptor involved in modulation of glutamate signaling. mGluR5 is implicated in hippocampal-dependent cognitive functions that are disrupted in schizophrenia, and we recently provided evidence of aberrant expression of mGluR5 protein in the postmortem schizophrenia hippocampus. Here, we set out to investigate the association between allelic and genotypic frequencies of two novel single nucleotide polymorphisms (SNPs) in GRM5 with schizophrenia, as well as the effects of these genetic variants on cognitive function and hippocampal volume in a well-selected schizophrenia case-control cohort.
Methods: rs60954128 [C>T] and rs3824927 [G>T] were genotyped by Sequenom MassARRAY in 268 schizophrenia and 268 control Caucasian individuals, using DNA from the Australian Schizophrenia Research Bank (ASRB). All participants completed a standard set of neuropsychological tests, and 78 controls/103 cases had high-resolution T1-weighted anatomical scans available (MPRAGE, Siements Avanto 1.5 Tesla). Scans were processed and hippocampal volumes extracted using Freesurfer v5.1. Chi-squared analyses were used to determine associations between allelic/genotypic frequencies and schizophrenia. The effects of diagnosis, genotype, and their interactive effects were examined for each cognitive measure and hippocampal volume using mixed design MANCOVA.
Results: Males with schizophrenia were more likely to carry minor alleles for rs60954128 than male controls (p=0.011). Genetic variants for this SNP also affected intelligence and delayed memory in males, and working memory in females with schizophrenia (p<0.042). rs60954128 variants significantly interacted with diagnosis in schizophrenia males affecting hippocampal volumes, with carriers of the minor allele showing significantly reduced right hippocampal volume relative to major allele homozygotes and controls (p=0.013). For rs3824927, schizophrenia males carrying the minor allele showed reduced intelligence, working and delayed memory scores (p<0.025), although allelic frequencies for this SNP were not different in schizophrenia compared to controls.
Conclusions: These findings converge with previous reports from animal models and postmortem brain studies to implicate GRM5 variants in the cognitive symptoms seen in patients with schizophrenia, with these effects potentially mediated by anatomical integrity of the hippocampus, and possibly occurring in a sex-specific manner. Further studies are now required to determine the functional and molecular consequences of these genetic variants, and the molecular pathways by which they operate to impact on hippocampal integrity, cognitive function and the genetic vulnerability to schizophrenia.