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

Liang, Wei; Yu, Hao; Su, Yi; Lu, Tianlan; Yan, Hao; Yue, Weihua; Zhang, Dai

doi:10.1038/s41398-020-0763-4

Cited by 17 publications

(6 citation statements)

References 36 publications

(44 reference statements)

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“…In CACNA1A , one probe (cg26554567) showed a significant decrease in DNA methylation in the low-dose haloperidol group (Δβ = −0.109, P = 1.382e-05) and the high-dose risperidone group (Δβ = −0.107, P = 4.339e-05). GRM7 has been reported to be a potential target gene for seven antipsychotics, including haloperidol and risperidone ( Liang et al, 2020 ). In this study, one probe (cg21032008) related to GRM7 showed a significant increase in DNA methylation (Δβ = 0.117, P = 0.0069) in the high-dose haloperidol group compared to the control group.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone

Nakachi

Kiyono

et al. 2021

Front. Mol. Neurosci.

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Accumulating evidence suggests that the epigenetic alterations induced by antipsychotics contribute to the therapeutic efficacy. However, global and site-specific epigenetic changes by antipsychotics and those shared by different classes of antipsychotics remain poorly understood. We conducted a comprehensive DNA methylation analysis of human neuroblastoma cells cultured with antipsychotics. The cells were cultured with low and high concentrations of haloperidol or risperidone for 8 days. DNA methylation assay was performed with the Illumina HumanMethylation450 BeadChip. We found that both haloperidol and risperidone tended to cause hypermethylation changes and showed similar DNA methylation changes closely related to neuronal functions. A total of 294 differentially methylated probes (DMPs), including 197 hypermethylated and 97 hypomethylated DMPs, were identified with both haloperidol and risperidone treatment. Gene ontology analysis of the hypermethylated probe-associated genes showed enrichment of genes related to the regulation of neurotransmitter receptor activity and lipoprotein lipase activity. Pathway analysis identified that among the DMP-associated genes, SHANK1 and SHANK2 were the major genes in the neuropsychiatric disorder-related pathways. Our data would be valuable for understanding the mechanisms of action of antipsychotics from an epigenetic viewpoint.

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Section: Discussionmentioning

confidence: 99%

Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone

Nakachi

Kiyono

et al. 2021

Front. Mol. Neurosci.

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“…As is shown in our results, in the frontal cortex, there are eQTL associations of rs2268490 with metabotropic glutamate receptor 7 ( GRM7 ), a critical actor in regulating synaptic glutamate transmission 23 . Besides, GRM7 has been found to be associated with the risk of schizophrenia and the treatment responses of antipsychotics 24 . Therefore, these findings may explain the biological mechanism of the differences in responses to antipsychotics in patients with different rs2268490 genotypes.…”

Section: Discussionmentioning

confidence: 99%

OXTR polymorphisms associated with severity and treatment responses of schizophrenia

Lv,

Hou,

Zhang

et al. 2024

Schizophr

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The mechanisms generating specific symptoms of schizophrenia remain unclear and genetic research makes it possible to explore these issues at a fundamental level. Taking into account the associations between the oxytocin system and social functions, which are apparently impaired in schizophrenia patients, we hypothesized that the oxytocin receptor gene (OXTR) might be associated with schizophrenia symptoms in both severity and responses to antipsychotics and did this exploratory positional study. A total of 2363 patients with schizophrenia (1181 males and 1182 females) included in our study were randomly allocated to seven antipsychotic treatment groups and received antipsychotic monotherapy for 6 weeks. Their blood DNA was genotyped for OXTR polymorphisms. Their symptom severity was assessed by Positive and Negative Syndrome Scale (PANSS), and the scores were transformed into seven factors (positive, disorganized, negative symptoms apathy/avolition, negative symptoms deficit of expression, hostility, anxiety and depression). Percentage changes in PANSS scores from baseline to week 6 were calculated to quantify antipsychotic responses. We found that OXTR polymorphisms were nominally associated with the severity of overall symptoms (rs237899, β = 1.669, p = 0.019), hostility symptoms (rs237899, β = 0.427, p = 0.044) and anxiety symptoms (rs13316193, β = −0.197, p = 0.038). As for treatment responses, OXTR polymorphisms were nominally associated with the improvement in negative symptoms apathy/avolition (rs2268490, β = 2.235, p = 0.0499). No association between severity or response to treatment and OXTR polymorphisms was found with statistical correction for multiplicity. Overall, our results highlighted the possibility of nominally significant associations of the OXTR gene with the severity and improvement in schizophrenia symptoms. Given the exploratory nature of this study, these associations are indicative of the role of the OXTR gene in the pathology of schizophrenia and may contribute to further elucidate the mechanism of specific symptoms of schizophrenia and to exploit antipsychotics more effective to specific symptoms.

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“…In particular, the rs2069062 has been included in the PharmGKB for clinical annotation. In addition, another SNP (rs9883258) was reported to be a potential marker for the therapeutic response of seven commonly used antipsychotic drugs in the Chinese Han population [33]. This trans-ethnic role of GRM7 in treatment response in patients with schizophrenia boosts our confidence in the authenticity of the identified risk signals.…”

Section: Discussionmentioning

confidence: 95%

Different responses to risperidone treatment in Schizophrenia: a multicenter genome-wide association and whole exome sequencing joint study

Zhao

et al. 2022

Transl Psychiatry

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Risperidone is routinely used in the clinical management of schizophrenia, but the treatment response is highly variable among different patients. The genetic underpinnings of the treatment response are not well understood. We performed a pharmacogenomic study of the treatment response to risperidone in patients with schizophrenia by using a SNP microarray -based genome-wide association study (GWAS) and whole exome sequencing (WES)-based GWAS. DNA samples were collected from 189 patients for the GWAS and from 222 patients for the WES after quality control in multiple centers of China. Antipsychotic response phenotypes of patients who received eight weeks of risperidone treatment were quantified with percentage change on the Positive and Negative Syndrome Scale (PANSS). The GWAS revealed a significant association between several SNPs and treatment response, such as three GRM7 SNPs (rs141134664, rs57521140, and rs73809055). Gene-based analysis in WES revealed 13 genes that were associated with antipsychotic response, such as GPR12 and MAP2K3. We did not identify shared loci or genes between GWAS and WES, but association signals tended to cluster into the GPCR gene family and GPCR signaling pathway, which may play an important role in the treatment response etiology. This study may provide a research paradigm for pharmacogenomic research, and these data provide a promising illustration of our potential to identify genetic variants underlying antipsychotic responses and may ultimately facilitate precision medicine in schizophrenia.

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

Cited by 17 publications

References 36 publications

Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone

Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone

OXTR polymorphisms associated with severity and treatment responses of schizophrenia

Different responses to risperidone treatment in Schizophrenia: a multicenter genome-wide association and whole exome sequencing joint study

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