A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia

Miyazawa, Atsuhiro; Kanahara, Nobuhisa; Kogure, Masanobu; Otsuka, Ikuo; Okazaki, Satoshi; Watanabe, Yoshinori; Yamasaki, Fumiaki; Nakata, Yusuke; Oda, Yasunori; Hishimoto, Akitoyo; Iyo, Masaomi

doi:10.1007/s11033-021-07019-z

Cited by 14 publications

(9 citation statements)

References 51 publications

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“…In fact, KO mice for GABRB2 (GABA type A receptor β 2 subunit) gene exhibit schizophrenia-like behavior and GABA interneurons dystrophy, astrocyte degeneration, and widespread microglia activation in frontotemporal corticolimbic regions, as well as an increase in ionized calcium-binding adaptor molecule 1 (Iba-1), a molecular biomarker of neuroinflammation [ 232 ]. As also shown in clinical studies, polymorphism of GABRB2 would confer not only susceptibility to the disorder but also resistance to antipsychotic treatment [ 233 ], probably due to the involvement of profound inflammatory alterations.…”

Section: Influence Of Inflammation On Synaptic Structures and Dendrit...mentioning

confidence: 91%

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

Bartolomeis¹,

Barone²,

Vellucci³

et al. 2022

Mol Neurobiol

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Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between the inflammatory background and two well-recognized functional and structural findings of schizophrenia pathophysiology: the dopamine-glutamate aberrant interaction and the alteration of dendritic spines architecture, both believed to be the “quantal” elements of cortical-subcortical dysfunctional network. In this systematic review, we tried to capture the major findings linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes under a direct and inverse translational perspective, a paramount picture that at present is lacking. The inflammatory effects on dopaminergic function appear to be bidirectional: the inflammation influences dopamine release, and dopamine acts as a regulator of discrete inflammatory processes involved in schizophrenia such as dysregulated interleukin and kynurenine pathways. Furthermore, the link between inflammation and glutamate is strongly supported by clinical studies aimed at exploring overactive microglia in schizophrenia patients and maternal immune activation models, indicating impaired glutamate regulation and reduced N-methyl-D-aspartate receptor (NMDAR) function. In addition, an inflammatory/immune-induced alteration of post-synaptic density scaffold proteins, crucial for downstream NMDAR signaling and synaptic efficacy, has been demonstrated. According to these findings, a significant increase in plasma inflammatory markers has been found in schizophrenia patients compared to healthy controls, associated with reduced cortical integrity and functional connectivity, relevant to the cognitive deficit of schizophrenia. Finally, the link between altered inflammatory/immune responses raises relevant questions regarding potential new therapeutic strategies specifically for those forms of schizophrenia that are resistant to canonical antipsychotics or unresponsive to clozapine.

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Section: Influence Of Inflammation On Synaptic Structures and Dendrit...mentioning

confidence: 91%

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

Bartolomeis¹,

Barone²,

Vellucci³

et al. 2022

Mol Neurobiol

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“…In addition, few reports have focused on GABA B receptors in patients with TRS in particular. We recently observed that the distribution of a SNP (rs10985765) that is present in the exon coding the cytoplasmic domain of GABBR2 differs between TRS patients and healthy controls with a nominal level of significance (Miyazawa et al, 2022), which may indicate that TRS patients may have some abnormality in GABA B signal transduction. In order to rigorously examine the relationships among the prolongation of the CSP, clozapine treatment, and patients with TRS, it is necessary to perform studies measuring the CSP in patients with other psychotic disorders (e.g.…”

Section: Discussionmentioning

confidence: 99%

The cortical silent period in schizophrenia: A systematic review and meta-analysis focusing on disease stage and antipsychotic medication

et al. 2022

Self Cite

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Background: Although numerous studies reported some changes of cortical silent period (CSP), an indicator of gamma-aminobutyric acid (GABA) function in central nervous system, in schizophrenia patients, it has been unknown how the disease stage and antipsychotic medication affect CSP values. Methods: The present study conducted a systematic review of previous literature comparing CSP between schizophrenia patients and healthy subjects, and then performed meta-analysis on the effects of (1) the disease stage and (2) antipsychotics on CSP. Results: (1) In the comparison of the disease stage comprising a total of 17 reports, there was no significant difference in CSP between patients under drug-naïve first-episode psychoses and healthy controls, or between patients with antipsychotic medication and healthy controls. (2) In the comparison of the antipsychotic class, patients treated with clozapine were longer in CSP compared to healthy controls. Patients treated with olanzapine/quetiapine or with other type of antipsychotics were not different from healthy controls. Regarding other type of antipsychotics, the iteration analysis after leaving out one literature showed that patients were shorter in CSP than healthy controls. Conclusion: The results showed that clozapine seems to surely prolong CSP, indicating the enhancement of GABA transmission via GABAB receptors, suggesting the possible relationship between the CSP prolongation by clozapine and its high efficacy in psychopathology. The finding of shorter CSP in patients with other type of antipsychotics was distinct from clozapine/olanzapine/quetiapine, but was difficult to interpret since this group included a variety of transcranial magnetic stimulation (TMS) methodologies and patients’ background.

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“…Notably, the gene’s polymorphisms were found to be associated with mild cognitive impairment [ 40 ] and metachronous liver cancer [ 41 ]. Similarly, other genes located at the 11 identified loci (e.g., ATXN1 , GABBR2 , SETX , CDH23 ) are also implicated in nervous system pathology but are not clearly linked to immunity and/or infectious disease response [ 42 , 43 , 44 , 45 , 46 ]. This result might indicate a certain relationship between nervous system function and COVID-19 severity; however, it is important to note that no significant overrepresentation of nervous system genes was identified at the associated loci.…”

Section: Discussionmentioning

confidence: 99%

Identification of Genetic Risk Factors of Severe COVID-19 Using Extensive Phenotypic Data: A Proof-of-Concept Study in a Cohort of Russian Patients

Щербак

Changalidis

Barbitoff

et al. 2022

Genes

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The COVID-19 pandemic has drawn the attention of many researchers to the interaction between pathogen and host genomes. Over the last two years, numerous studies have been conducted to identify the genetic risk factors that predict COVID-19 severity and outcome. However, such an analysis might be complicated in cohorts of limited size and/or in case of limited breadth of genome coverage. In this work, we tried to circumvent these challenges by searching for candidate genes and genetic variants associated with a variety of quantitative and binary traits in a cohort of 840 COVID-19 patients from Russia. While we found no gene- or pathway-level associations with the disease severity and outcome, we discovered eleven independent candidate loci associated with quantitative traits in COVID-19 patients. Out of these, the most significant associations correspond to rs1651553 in MYH14p = 1.4 × 10−7), rs11243705 in SETX (p = 8.2 × 10−6), and rs16885 in ATXN1 (p = 1.3 × 10−5). One of the identified variants, rs33985936 in SCN11A, was successfully replicated in an independent study, and three of the variants were found to be associated with blood-related quantitative traits according to the UK Biobank data (rs33985936 in SCN11A, rs16885 in ATXN1, and rs4747194 in CDH23). Moreover, we show that a risk score based on these variants can predict the severity and outcome of hospitalization in our cohort of patients. Given these findings, we believe that our work may serve as proof-of-concept study demonstrating the utility of quantitative traits and extensive phenotyping for identification of genetic risk factors of severe COVID-19.

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A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia

Cited by 14 publications

References 51 publications

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

The cortical silent period in schizophrenia: A systematic review and meta-analysis focusing on disease stage and antipsychotic medication

Identification of Genetic Risk Factors of Severe COVID-19 Using Extensive Phenotypic Data: A Proof-of-Concept Study in a Cohort of Russian Patients

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