Genetic Variation in <i>KCNH2</i> Associated With Expression in the Brain of a Unique hERG Isoform Modulates Treatment Response in Patients With Schizophrenia

Apud, José; Zhang, Fengyu; Decot, Heather; Bigos, Kristin L.; Weinberger, Daniel R.

doi:10.1176/appi.ajp.2012.11081214

Cited by 55 publications

(54 citation statements)

References 24 publications

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“…All these patients were selfreported Caucasians of European ancestry and were diagnosed with chronic schizophrenia using DSM-IV criteria. All individuals volunteered to participate in a double-blind, placebo-controlled cross-over study with standard doses of atypical antipsychotics, including olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole (Apud et al, 2012). The program typically enrolled patients who previously had adequate trials of standard antipsychotic medication interventions, which were only partially effective in decreasing their symptoms (see Supplementary Materials and Methods).…”

Section: Response To Antipsychotic Treatmentmentioning

confidence: 99%

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Blasi

Selvaggi

Fazio

et al. 2015

Neuropsychopharmacol

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Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n ¼ 63 and n ¼ 54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.

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Section: Response To Antipsychotic Treatmentmentioning

confidence: 99%

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Blasi

Selvaggi

Fazio

et al. 2015

Neuropsychopharmacol

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“…Fifty-four patients with schizophrenia, admitted to the Clinical Brain Disorders Branch schizophrenia research inpatient unit at the NIH Clinical Center between 1998 and 2010, were included in this study (DR Weinberger, PI; see Apud et al, 2012). All subjects were Caucasian of European ancestry and were diagnosed with chronic schizophrenia using DSM-IV criteria.…”

Section: Antipsychotic Treatment Response Study Design and Subjectsmentioning

confidence: 99%

“…Subgroup 1 (N ¼ 35) underwent a sequence of 4 weeks of coded placebo followed by 4 weeks of a coded standard atypical antipsychotic. Subgroup 2 (N ¼ 19) underwent the inverse sequence (ie, after a similar open medication and taper period, they received standard atypical antipsychotic treatment for 4 weeks followed by placebo for 4 weeks; (as described previously, Apud et al, 2012)). Because of the highly supervised and structured nature of the NIMH inpatient environment, most patients tolerated the 4 weeks of placebo well.…”

Section: Antipsychotic Treatment Response Study Design and Subjectsmentioning

confidence: 99%

“…Pharmacogenetic studies of inter-individual variation in drug response have emerged as potentially powerful tools for improving therapeutic outcomes in psychiatry (Malhotra et al, 2012a;Lotrich, 2012), through maximizing efficacy and minimizing antipsychotic side effects (Malhotra et al, 2012b). Although dopamine-serotonin receptor antagonism is the primary pharmacological target of antipsychotic drug action (Snyder, 1981;Kapur and Mamo, 2003), and polymorphisms in the dopamine D2 receptor and serotonin 5HT2C receptor have been associated with clinical response and adverse side effects (Giegling et al, 2013;, recent pharmacogenetic studies highlight targets outside of the dopaminergic/serotonergic system, including NRXN1 (Souza et al, 2010;Lett et al, 2011), KCNH2, GSK3, AKT1, and GRM8, as potential predictors of treatment response (Apud et al, 2012;Souza et al, 2008;Need et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, trend significance, lack of placebo control, and lack of examination of effects of treatment on symptom subcategories limits interpretation of these data and warrants independent replication. In this study, we conducted a pharmacogenetic analysis of antipsychotic drug response in patients with schizophrenia (N ¼ 54) in the Clinical Brain Disorders Branch/National Institute of Mental Health (NIMH) double-blind, placebocontrolled inpatient crossover trial and examined for association of the same two SNPs in NRXN1 (rs12467557 and rs10490162) with treatment response as measured by the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1991;Apud et al, 2012). In a secondary analysis, we evaluated association in the NIMH-sponsored multicenter Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study, though the CATIE trial is a comparative efficacy trial and not a placebo-controlled therapeutic trial.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia

Jenkins

Apud

Zhang

et al. 2014

Neuropsychopharmacol

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Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs.

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Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

et al. 2019

Autism Research

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Autism is a common neurodevelopmental disorder with a moderate to a high degree of heritability, but only a few common genetic variants that explain the heritability have been associated. We performed a genome‐wide transmission disequilibrium test analysis of a newly genotyped autism case–parent triad samples (127 trios) in Han Chinese, identified top association signals at multiple single nucleotide polymorphisms (SNPs), including rs9839376 (OR = 2.59, P = 1.27 × 10−05) at KCNMB2, rs6044680 (OR = 0.319, P = 4.82 × 10−05) and rs7274133 (OR = 0.313, P = 3.22 × 10−05) at PCSK2, and rs310619 (OR = 2.40, P = 7.44 × 10−05) at EEF1A2. Furthermore, a genome‐wide combined P‐value of individual SNPs in two independent case–parent triad samples (total 402 triads, n = 1,206) identified SNPs at EGFLAM, ZDHHC2, AGBL1, and SNX29 as additional association signals for autism. While none of these signals achieved a genome‐wide significance in the two samples of our study, they have been reported in a previous genome‐wide association study of neuropsychiatric disorders, and the majority of these SNP have a significant cis‐regulatory association with mRNA in human tissues (false discovery rate (FDR) < 0.05). Our study warrants further study or replication with additional sample for association with autism and other neuropsychiatric disorders. Autism Res 2020, 13: 382–396. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Autism is a common neurodevelopmental disorder, heritable, but only a few common genetic variants that explain the heritability have been associated. We conducted a genome‐wide association study with two cohorts of autism case–parent triad samples in Han Chinese and identified multiple single nucleotide polymorphisms that were reported as strong association signals in a previous genome‐wide association study of other neuropsychiatric disorders or related traits. Our study provides evidence for shared genetic variants among autism and other neuropsychiatric disorders.

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Genetic Variation in KCNH2 Associated With Expression in the Brain of a Unique hERG Isoform Modulates Treatment Response in Patients With Schizophrenia

Cited by 55 publications

References 24 publications

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia

Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

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