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Variants of GRM7 as risk factor and response to antipsychotic therapy in schizophrenia.

ABSTRACT: Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the relationship between the GRM7 variants and the risk of schizophrenia is still uncertain, and there are significant individual variations in response to the antipsychotic drugs. In order to identify susceptible gene and drug-response-related markers, 2413 subjects in our research were chosen for determining drug-response-related markers in schizophrenia. The rs1516569 variant (OR?=?0.95, P?-4) was a significant risk factor, and a single-nucleotide polymorphism of GRM7 gene- rs9883258 (OR?=?0.84, P?=?2.18?×?10^-3) has been determined as potential biomarkers for therapeutic responses of seven commonly used antipsychotic drugs (aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone and ziprasidone) in Chinese Han population; Significant associations with treatment response for several single-nucleotide polymorphisms in every antipsychotic drugs, such as rs779746 (OR?=?1.39, P?=?0.03), rs480409 (OR?=?0.73, P?=?0.04), rs78137319 (OR?=?3.09, P?=?0.04), rs1154370 (OR?=?1.51, P?=?0.006) have been identified in our study. Hence our research elucidates that GRM7 variants play the critical role of predicting the risk of schizophrenia and antipsychotic effect of seven common drugs.

SUBMITTER: Liang W

PROVIDER: S-EPMC7054263 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Variants of GRM7 as risk factor and response to antipsychotic therapy in schizophrenia.

Liang Wei W Yu Hao H Su Yi Y Lu Tianlan T Yan Hao H Yue Weihua W Zhang Dai D

Translational psychiatry 20200303 1

Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the relationship between the GRM7 variants and the risk of schizophrenia is still uncertain, and there are significant individual variations in response to the antipsychotic drugs. In order to identify susceptible gene and drug-response-related markers, 2413 subjects in our research were chosen for determining drug-response-related mar ...[more]

PMID: 32127521

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Project description:Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36?989 cases and 113?075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.US National Institutes of Health.

Project description:BackgroundMany people with schizophrenia do not reach a satisfactory clinical response with a standard dose of an initially prescribed antipsychotic drug. In such cases, clinicians face the dilemma of increasing the antipsychotic dose in order to enhance antipsychotic efficacy.ObjectivesTo examine the efficacy of increasing antipsychotic dose compared to keeping the same dose in the treatment of people with schizophrenia who have not responded (as defined in the individual studies) to an initial antipsychotic drug trial. We also examine the adverse effects associated with such a procedure.Search methodsWe searched the Cochrane Schizophrenia Group Trials Register (10 June 2014, 6 October 2015, and 30 March 2017). We examined references of all included studies for further trials.Selection criteriaAll relevant randomised controlled trials (RCTs), reporting useable data, comparing increasing the antipsychotic dose rather than maintaining the original dose for people with schizophrenia who do not respond to their initial antipsychotic treatment.Data collection and analysisAt least two review authors independently extracted data . We analysed dichotomous data using relative risks (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their 95% CI. We assessed risk of bias for included studies and used GRADE to create a 'Summary of findings' table.Main resultsTen relevant RCTs with 675 participants are included in this review. All trials were double blind except one single blind. All studies had a run-in phase to confirm they did not respond to their initial antipsychotic treatment. The trials were published between 1980 and 2016. In most studies the methods of randomisation, allocation and blinding were poorly reported. In addition sample sizes were often small, limiting the overall quality of the evidence. Overall, no clear difference was found between groups in terms of the number of participants who showed clinically relevant response (RR 1.09, 95% CI 0.86 to 1.40, 9 RCTs, N = 533, low-quality evidence), or left the study early due to adverse effects (RR 1.63, 95% CI 0.52 to 5.07, very low quality evidence), or due to any reason (RR 1.30, 95% CI 0.89 to 1.90, 5 RCTs, N = 353, low-quality evidence). Similarly, no clear difference was found in general mental state as measured by PANSS total score change (MD -1.44, 95% CI -6.85 to 3.97, 3 RCTs, N = 258, very low quality evidence). At least one adverse effect was equivocal between groups (RR 0.91, 95% CI 0.55 to 1.50, 2 RCTs, N = 191, very low quality evidence). Data were not reported for time in hospital or quality-of-life outcomes. Finally, subgroup and sensitivity analyses did not show any effect on the primary outcome but these analyses were clearly underpowered.Authors' conclusionsCurrent data do not show any clear differences between increasing or maintaining the antipsychotic dose for people with schizophrenia who do not respond to their initial antipsychotic treatment. Adverse effect reporting was limited and poor. There is an urgent need for further trials in order to determine the optional treatment strategy in such cases.

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Variants of GRM7 as risk factor and response to antipsychotic therapy in schizophrenia.

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Variants of GRM7 as risk factor and response to antipsychotic therapy in schizophrenia.

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