Effects of common GRM5 genetic variants on cognition, hippocampal volume and mGluR5 protein levels in schizophrenia

GRM5(coding for metabotropic glutamate receptor5, mGluR5) is a promising target for the treatment of cognitivedeficits in schizophrenia, but there has been little investigationof its association with cognitive and brain phenotypes withinthis disorder. We examined the effects of common geneticvariation inGRM5with cognitive function, hippocampalvolume, and hippocampal mGluR5 protein levels inschizophrenia patients relative to healthy controls. TwoindependentGRM5variants rs60954128 [C > T] andrs3824927 [G > T] were genotyped in a schizophreniacase/control cohort (n=249/261). High-resolution ana-tomical brain scans were available for a subset of thecohort (n=103 schizophrenia /78 control). All partici-pants completed a standard set of neuropsychologicaltests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippocampal mGluR5 protein levels were exam-ined among individuals of differentGRM5genotypes.Schizophrenia minor allele carriers of rs60954128 had re-duced right hippocampal volume relative to healthy controlsof the same genotype (−12.3%); this effect was exaggerated inmales with schizophrenia (−15.6%). For rs3824927,compared to major allele homozygotes, minor allele car-riers with schizophrenia had lower IntelligenceQuotients (IQ). Examination in hippocampal postmortemtissue showed no difference in mGluR5 protein expressionaccording to genotype for either rs60954128 or rs3824927.While these genetic variants inGRM5were associatedwith cognitive impairments and right hippocampal vol-ume reduction in schizophrenia, they did not affect pro-tein expression. Further study of these mechanisms mayhelp to delineate new targets for the treatment of cog-nitive deficits in schizophrenia, and may be relevant toother disorders.