Genetic association analysis of N‐methyl‐<scp>d</scp>‐aspartate receptor subunit gene <i>GRIN2B</i> and clinical response to clozapine

Taylor, Danielle L.; Tiwari, Arun K.; Lieberman, Jeffrey A.; Potkin, Steven G.; Meltzer, Herbert Y.; Knight, Jo; Remington, Gary; Müller, Daniel J.; Kennedy, James L.

doi:10.1002/hup.2519

Cited by 19 publications

(10 citation statements)

References 141 publications

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“…De novo missense mutations in critical TM and ABD regions, or frameshift or nonsense mutations leading to truncated proteins, were absent from SCZ patient cohorts. Rather, these cohorts reveal missense mutations in the ATD or CTD domains where ExAC allele frequencies trend higher and association with SCZ may be variable or low (27), consistent with a lack of association between clozapine response and GRIN2B variants in a SCZ patient population (51). Notably, the agonist binding domain of GluN2B exhibits significant intolerance to mutation based on absence of these variants in ExAC control exomes (Table 1, Fig.…”

Section: Discussionmentioning

confidence: 57%

Human GRIN2B variants in neurodevelopmental disorders

Chen

Myers

et al. 2016

Journal of Pharmacological Sciences

191

163

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The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-D-aspartate receptor (NMDAR) gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders. Studies that provide functional analysis of variants are still lacking, however current analysis of de novo variants that segregate with disease cases such as intellectual disability, developmental delay, ASD or epileptic encephalopathies reveal altered NMDAR function. Here, we summarize the current reports of disease-associated variants in GRIN2B from patients with multiple neurodevelopmental disorders, and discuss implications, highlighting the importance of functional analysis and precision medicine therapies.

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Section: Discussionmentioning

confidence: 57%

Human GRIN2B variants in neurodevelopmental disorders

Chen

Myers

et al. 2016

Journal of Pharmacological Sciences

191

163

View full text Add to dashboard Cite

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“…Spurious and contrasting results are available for other genes in the glutamatergic system, such as the glutamate ionotropic receptor delta type subunit 2 ( GRID2 ) (Stevenson et al, 2016) and the glutamate ionotropic N -methyl- D -aspartate receptor 2B subunit (Hong et al, 2001; Taylor et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Treatment-Resistant Schizophrenia: Genetic and Neuroimaging Correlates

et al. 2019

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Schizophrenia is a severe neuropsychiatric disorder that affects approximately 0.5–1% of the population. Response to antipsychotic therapy is highly variable, and it is not currently possible to predict those patients who will or will not respond to antipsychotic medication. Furthermore, a high percentage of patients, approximately 30%, are classified as treatment-resistant (treatment-resistant schizophrenia; TRS). TRS is defined as a non-response to at least two trials of antipsychotic medication of adequate dose and duration. These patients are usually treated with clozapine, the only evidence-based pharmacotherapy for TRS. However, clozapine is associated with severe adverse events. For these reasons, there is an increasing interest to identify better targets for drug development of new compounds and to establish better biomarkers for existing medications. The ability of antipsychotics to improve psychotic symptoms is dependent on their antagonist and reverse agonist activities at different neuroreceptors, and some genetic association studies of TRS have focused on different pharmacodynamic factors. Some genetic studies have shown an association between antipsychotic response or TRS and neurodevelopment candidate genes, antipsychotic mechanisms of action (such as dopaminergic, serotonergic, GABAergic, and glutamatergic) or pharmacokinetic factors (i.e., differences in the cytochrome families). Moreover, there is a growing body of literature on the structural and functional neuroimaging research into TRS. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify resistant patients earlier. Studies examining the neuropharmacological mechanisms of antipsychotics, including clozapine, can help to improve our knowledge of their action on the central nervous system, with further implications for the discovery of biomarkers and the development of new treatments. The identification of the underlying mechanisms of TRS is a major challenge for developing personalized medicine in the psychiatric field for schizophrenia treatment. The main goal of precision medicine is to use genetic and brain-imaging information to improve the safety, effectiveness, and health outcomes of patients via more efficiently targeted risk stratification, prevention, and tailored medication and treatment management approaches. The aim of this review is to summarize the state of art of pharmacogenetic, pharmacogenomic and neuroimaging studies in TRS.

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“…In TRS, a handful of studies have investigated glutamate system genes in relation to clozapine response. These have largely focused on variants in GRIN2B , which codes for the 2B subunit of the glutamate N -methyl-d-aspartate receptor 65. Further work is needed to clarify any potential role for the glutamate system in the pathophysiology of TRS and clozapine response.…”

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 99%

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

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Up to 30% of people with schizophrenia do not respond to two (or more) trials of dopaminergic antipsychotics. They are said to have treatment-resistant schizophrenia (TRS). Clozapine is still the only effective treatment for TRS, although it is underused in clinical practice. Initial use is delayed, it can be hard for patients to tolerate, and clinicians can be uncertain as to when to use it. What if, at the start of treatment, we could identify those patients likely to respond to clozapine – and those likely to suffer adverse effects? It is likely that clinicians would feel less inhibited about using it, allowing clozapine to be used earlier and more appropriately. Genetic testing holds out the tantalizing possibility of being able to do just this, and hence the vital importance of pharmacogenomic studies. These can potentially identify genetic markers for both tolerance of and vulnerability to clozapine. We aim to summarize progress so far, possible clinical applications, limitations to the evidence, and problems in applying these findings to the management of TRS. Pharmacogenomic studies of clozapine response and tolerability have produced conflicting results. These are due, at least in part, to significant differences in the patient groups studied. The use of clinical pharmacogenomic testing – to personalize clozapine treatment and identify patients at high risk of treatment failure or of adverse events – has moved closer over the last 20 years. However, to develop such testing that could be used clinically will require larger, multicenter, prospective studies.

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Genetic association analysis of N‐methyl‐d‐aspartate receptor subunit gene GRIN2B and clinical response to clozapine

Cited by 19 publications

References 141 publications

Human GRIN2B variants in neurodevelopmental disorders

Human GRIN2B variants in neurodevelopmental disorders

Treatment-Resistant Schizophrenia: Genetic and Neuroimaging Correlates

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

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