A polymorphism in the glutamate metabotropic receptor 7 is associated with cognitive deficits in the early phases of psychosis.

Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway.

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Déclaration de conflit d'intérêts

Declaration of competing interest Dr. Joober reports to be a speaker and/or consulting committee member for Pfizer, Janssen, BMS, Sunovian, Myelin, Otsuka, Lundbeck, shire and Perdue, and to have received grants from Janssen, BMS, Otsuka, Lundbeck, Astra Zeneca and HLS, and to have royalties from Henry Stewart talks, all outside the submitted work. Dr. Malla served as a research consultant to and gave lectures at conferences supported by Lundbeck and Otsuka and was on an advisory board meeting for the same two companies for which he received honoraria. Pr. Krebs has received honoraria from and participated in advisory boards or did educational conference for F. Hoffmann-La Roche, Janssen Cilag and Otsuka-Lundbeck. She received financial support for investigator-driven educational initiative from Eisai, Janssen Cilag and Otsuka-Lundbeck. Dr. Lepage reports grants from Otsuka Lundbeck Alliance, personal fees from Otsuka Canada, personal fees from Lundbeck Canada, grants and personal fees from Janssen, personal fees from MedAvante-Prophase, personal fees from Amplexor, outside the submitted work. Dr. Chaumette has received speaking fees from Janssen Cilag, outside the submitted work. All authors declare they have no conflict of interest related to this article. The contributing Group members (ICAAR study group) declare no conflict of interest.