Effects of common GRM5 genetic variants on cognition, hippocampal volume and mGluR5 protein levels in schizophrenia
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, compared 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 were associated with cognitive impairments and right hippocampal volume reduction in schizophrenia, they did 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.
KeywordsMetabotropic glutamate receptor 5 mGluR5 GRM5 Schizophrenia Case-control IQ
This study was supported by a Grant-in-Aid held by Authors NM, KN and FF and the Daniel Beck Award held by Author NM, from the Schizophrenia Research Institute. The study used samples and data from the Australian Schizophrenia Research Bank (ASRB), funded by the Australian National Health and Medical Research Council (NHMRC) Enabling Grant (No. 386500) held by V. Carr, U. Schall, R. Scott, A. Jablensky, B. Mowry, P. Michie, S. Catts, F. Henskens and C. Pantelis (Chief Investigators), and the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, as well the Schizophrenia Research Institute, using an infrastructure grant from the NSW Ministry of Health. Authors NM and JA were supported by Ian Scott Scholarships from Australian Rotary Health. Author NT was supported by an Australian Postgraduate Award. Author MG was supported by an Australian National Health and Medical Research Council (NHMRC) Biomedical Career Development Fellowship (1061875). Postmortem brain tissues were received from the NSW Tissue Resource Centre, which is supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism [NIH (NIAA) R24AA012725]. The authors wish to thank P. Bitter and B. Yamasani from the Australian Cancer Research Foundation at The Garvan Institute of Medical Research, Sydney for their assistance with the MassARRAY genotyping assays, as well as A.M. Shepherd and I.C. Gould for assistance with structural imaging and Freesurfer processing. All authors report no financial relationships with commercial interests.
Compliance with ethical standards
Conflicts of interest
All authors declare that they have no conflicts of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all patients for being included in the study
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