Association Study Indicates a Protective Role of Phosphatidylinositol-4-Phosphate-5-Kinase against Tardive Dyskinesia

Fedorenko, Olga Yu; Loonen, Anton J. M.; Läng, Florian; Toshchakova, Valentina A.; Boyarko, E.G.; Semke, A.; Бохан, Н. А.; Govorin, N.V.; Aftanas, Lyubomir I.; Ivanova, Svetlana A.

doi:10.1093/ijnp/pyu098

Cited by 23 publications

(20 citation statements)

References 32 publications

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“…In TD positive cases a higher homocysteine level is reported (Lerner et al, 2005), thus the nominal association of MiRSNP rs4846049 in MTHFR in our study may also have a functional basis. The observed association of MiRSNP rs10734041 in PIP4K2A is consistent with a prior reported association with TD in a Caucasian ancestry sample (Fedorenko et al, 2014). Further, PIP4K2A is involved in G-protein coupled receptor mediated signaling and may provide protection against apoptosis and the stress response (van den Bout and Divecha, 2009).…”

Section: Discussionsupporting

confidence: 91%

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

John

Bhatia

Kukshal

et al. 2016

Schizophrenia Research

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MicroRNAs (miRNAs) bind to 3′UTRs of genes and negatively regulate their expression. With ~50% of miRNAs expressing in the brain, they play an important role in neuronal development, plasticity, cognition and neurological disorders. Conserved miRNA targets are present in > 60% genes in humans and are under evolutionary pressure to maintain pairing with miRNA. However, such binding may be affected by genetic variant(s) in the target sites (MiRSNPs), thereby altering gene expression. Differential expression of a large number of genes in postmortem brains of schizophrenia (SZ) patients compared to controls has been documented. Thus studying the role of MiRSNPs which are underinvestigated in SZ becomes attractive. We systematically selected 35 MiRSNPs with predicted functional relevance in 3′UTRs of genes shown previously to be associated with SZ, genotyped and tested their association with disease, using independent discovery and replication samples (total n = 1017 cases; n = 1073 controls). We also explored genetic associations with two sets of quantitative traits, namely tardive dyskinesia (TD) and cognitive functions disrupted in SZ in subsets of the study cohort. In the primary analysis, a significant association of MiRSNP rs7430 at PPP3CC was observed with SZ in the discovery and the replication samples [discovery: P = 0.01; OR (95%CI) 1.24 (1.04–1.48); replication: P = 0.03; OR (95%CI) 1.20 (1.02–1.43)]. In the exploratory analyses, five SNPs were nominally associated with TD (P values 0.04–0.004). Separately, 12 SNPs were associated with one or more of the eight cognitive domains (P values 0.05–0.003). These associations, particularly the SNP at PPP3CC merit further investigations.

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Section: Discussionsupporting

confidence: 91%

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

John

Bhatia

Kukshal

et al. 2016

Schizophrenia Research

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“…Variants previously found to be associated with TD were meta-analyzed with results from the current GWAS (Supplementary Table 11). 10,17,21,22,37–45 The following variants were replicated in the current study CYP1A2 (N = 1725, P = 0.018), DRD1 (N = 1788, P = 0.045), GRIN2A (N = 1837, P = 0.012), GRIN2B (N = 1057, P = 0.0018), HSPG2 (N = 1572, P = 0.0051), and DPP6 (N = 1701, P = 0.00068). These genes implicated pathways involving drug metabolism, dopamine, and glutamate.…”

Section: Resultsmentioning

confidence: 99%

“…36 Finally, variants previously associated with TD were compared with the current GWAS results. 10,17,21,22,37–45 Detailed methodological approaches are further reported in the Supplementary Information included with the current report.…”

Section: Methodsmentioning

confidence: 99%

Genome Wide Study of Tardive Dyskinesia in Schizophrenia

Lam

Lim

Tay

et al. 2018

Preprint

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Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of orofacial regions and extremities. Patients treated with antipsychotics typically present with TD symptomatology. Here, we conducted the largest GWAS of TD to date, by meta-analyzing samples of East-Asian, European, and African-American ancestry, followed by analyses of biological pathways and polygenic risk with related phenotypes. We identified a novel locus and three suggestive loci, implicating immune-related pathways. Through integrating trans-ethnic fine-mapping, we identified putative credible causal variants for three of the loci. Multivariate analyses of polygenic risk for TD supports the genetic susceptibility of TD, with relatively lower allele frequencies variants being associated with TD, beyond that of antipsychotic medication. Together, these findings provide new insights into the genetic architecture and biology of TD.

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“…While an association between some genetic polymorphisms85,86 and TD has been described in patients with schizophrenia, there is no consensus about a genetic predisposition to TD 87. On the other hand, several clinical variables have consistently predicted TD occurrence in schizophrenia in observational studies, RCTs, and reviews; these include anticholinergic medication; older age; intermittent antipsychotic treatment; high cumulative dose; higher negative, cognitive, and affective symptoms; and early movement side effects 88–91.…”

Section: Methodsmentioning

confidence: 99%

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

Solmi

Murru

Pacchiarotti

et al. 2017

TCRM

324

244

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Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis.

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Association Study Indicates a Protective Role of Phosphatidylinositol-4-Phosphate-5-Kinase against Tardive Dyskinesia

Cited by 23 publications

References 32 publications

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

Genome Wide Study of Tardive Dyskinesia in Schizophrenia

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

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