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

Authors: Natalie Matosin, Kelly Anne Newell, Yann Quidé, Jessica Lee Andrews, Nina Teroganova, Melissa Jayne Green† and Francesca Fernandez†*

Affiliations: Faculty of Science, Medicine and Health, Faculty of Social Sciences, and the Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia. School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. Neuroscience Research Australia, Sydney, Australia. School of Science, Faculty of Health Sciences, Australian Catholic University, Brisbane, Australia † These authors contributed equally

ABSTRACT: GRM5 (coding for metabotropic glutamate receptor 5, mGluR5) is a promising target for the treatment of cognitive deficits in schizophrenia, but there has been little investigation of its association with cognitive and brain phenotypes within this disorder. We examined the effects of common genetic variation in GRM5 with cognitive function, hippocampal volume, and hippocampal mGluR5 protein levels in schizophrenia patients relative to healthy controls. Two independent GRM5 variants rs60954128 [C>T] and rs3824927 [G>T] were genotyped in a schizophrenia case/control cohort (n=249/261). High-resolution anatomical brain scans were available for a subset of the cohort (n=103 schizophrenia /78 control). All participants completed a standard set of neuropsychological tests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippocampal mGluR5 protein levels were examined among individuals of different GRM5 genotypes. Schizophrenia minor allele carriers of rs60954128 had reduced right hippocampal volume relative to healthy controls of the same genotype (-12.3%); this effect was exaggerated in males with schizophrenia (-15.6%). For rs3824927, relative to major allele homozygotes, minor allele carriers with schizophrenia had lower Intelligence Quotients (IQ). Examination in hippocampal postmortem tissue showed no difference in mGluR5 protein expression according to genotype for either rs60954128 or rs3824927. While these genetic variants in GRM5 appear to be associated with cognitive impairments and right hippocampal volume reduction in schizophrenia, they do not affect protein expression. Further study of these mechanisms may help to delineate new targets for the treatment of cognitive deficits in schizophrenia, and may be relevant to other disorders.

Keywords: metabotropic glutamate receptor 5, mGluR5, GRM5, schizophrenia, case-control, IQ


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