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Genetic etiology of schizophrenia is poorly understood despite large genome-wide association data. Long non-coding RNAs (lncRNAs) with a probable regulatory role are emerging as important players in neuro-psychiatric disorders including schizophrenia. Prioritising important lncRNAs and analyses of their holistic interaction with their target genes may provide insights into disease biology/etiology. Of the 3843 lncRNA SNPs reported in schizophrenia GWASs extracted using lincSNP 2.0, we prioritised n = 247 based on association strength, minor allele frequency and regulatory potential and mapped them to lncRNAs. lncRNAs were then prioritised based on their expression in brain using lncRBase, epigenetic role using 3D SNP and functional relevance to schizophrenia etiology. 18 SNPs were finally tested for association with schizophrenia (n = 930) and its endophenotypes-tardive dyskinesia (n = 176) and cognition (n = 565) using a case-control approach. Associated SNPs were characterised by ChIP seq, eQTL, and transcription factor binding site (TFBS) data using FeatSNP. Of the eight SNPs significantly associated, rs2072806 in lncRNA hsaLB&#95;IO39983 with regulatory effect on BTN3A2 was associated with schizophrenia (p = 0.006); rs2710323 in hsaLB&#95;IO&#95;2331 with role in dysregulation of ITIH1 with tardive dyskinesia (p < 0.05); and four SNPs with significant cognition score reduction (p < 0.05) in cases. Two of these with two additional variants in eQTL were observed among controls (p < 0.05), acting likely as enhancer SNPs and/or altering TFBS of eQTL mapped downstream genes. This study highlights important lncRNAs in schizophrenia and provides a proof of concept of novel interactions of lncRNAs with protein-coding genes to elicit alterations in immune/inflammatory pathways of schizophrenia., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Genetic perturbations in dopamine neurotransmission and calcium signaling pathways are implicated in the etiology of schizophrenia. We aimed to test the association of a functional splice variant each in Dopamine β-Hydroxylase (DBH; rs1108580) and Calcium voltage-gated channel subunit alpha1 C (CACNA1C; rs1006737) genes in these pathways with schizophrenia (506 cases, 443 controls); Abnormal Involuntary Movement Scale (AIMS) scores in subjects assessed for tardive dyskinesia (76 TD-positive, 95 TD-negative) and Penn Computerized Neurocognitive Battery (PennCNB) scores (334 cases, 234 controls). The effect of smoking status and SNP genotypes on AIMS scores were assessed using ANOVA; health status and SNP genotypes on three performance functions of PennCNB cognitive domains were assessed by ANCOVA with age and sex as covariates. Association with Positive and Negative Syndrome Scale (PANSS) scores in the TD cohort and cognitive scores in healthy controls of the cognition cohort were tested by linear regression. None of the markers were associated with schizophrenia. Smoking status [F(2, 139) = 10.6; p = 5 × 10 -5 ], rs1006737 [F(2, 139) = 7.1; p = 0.001], TD status*smoking [F(2, 139) = 8.0; p = 5.0 × 10 -4 ] and smoking status*rs1006737 [F(4, 139) = 2.7; p = 0.03] had an effect on AIMS score. Furthermore, rs1006737 was associated with orofacial [F(2, 139) = 4.6; p = 0.01] and limb-truncal TD [(F(2, 139) = 3.8; p = 0.02]. Main effect of rs1108580 on working memory processing speed  [F(2, 544) = 3.8; p = 0.03] and rs1006737 on spatial ability efficiency  [F(1, 550) = 9.4; p = 0.02] was identified. Health status*rs1006737 interaction had an effect on spatial memory processing speed  [F(1, 550) = 6.9; p = 0.01]. Allelic/genotypic association (p = 0.01/0.03) of rs1006737 with disorganized/concrete factor and allelic association of rs1108580 (p = 0.04) with a depressive factor of PANSS was observed in the TD-negative subcohort. Allelic association of rs1006737 with sensorimotor dexterity accuracy (p = 0.03), attention efficiency (p = 0.05), and spatial ability efficiency (p = 0.02); allelic association of rs1108580 with face memory accuracy (p = 0.05) and emotion efficiency (p = 0.05); and allelic/genotypic association with emotion accuracy (p = 0.003/0.009) were observed in healthy controls of the cognition cohort. These association findings may have direct implications for personalized medicine and cognitive remediation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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. Post-hoc analysis revealed that SNPs harbored in TNFRSF1B and CALCOCO1 independently conferred three-fold increase in TD risk, beyond clinical risk factors like Age of onset and Duration of illness to schizophrenia. Further work is necessary to replicate loci that are reported in the study and evaluate the polygenic architecture underlying TD.

Objective: The aim of the study is to test the association of a functional variant each in DRD2 and COMT genes with schizophrenia and its endophenotypes., Basic Methods: Effect of two functional variants rs1076560 in DRD2 and rs4680 in COMT on (1) schizophrenia (502 cases, 448 controls) diagnosed by Diagnostic and Statistical Manual of Mental Disorders-IV criteria and in subsets with (2) tardive dyskinesia (80 positive, 103 negative), assessed by Abnormal Involuntary Movement Scale (AIMS), positive and negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) and (3) cognition (299 cases, 245 controls), estimated by Penn Computerized Neurocognitive Battery, were analysed either using analysis of variance (ANOVA) or regression analysis., Main Results: No association of two SNPs with schizophrenia, but association of rs4680 (P < 0.05) with tardive dyskinesia was observed. On ANOVA, main effect of smoking [F(2,148) = 16.3; P = 3.9 × 10]; rs4680 [F(2,148) = 3.3; P = 0.04] and interaction effect of tardive dyskinesia-status*Smoking [F(2,148) = 5.4, P = 0.006]; Smoking*rs1076560 [F(3,148) = 3.6; P = 0.01]; Smoking*rs4680 [F(4,148) = 5.3; P = 4.7 × 10] were significant with AIMS tardive dyskinesia score. The main effect of rs1076560 [F(2,148) = 4.5; P = 0.013] and rs4680 [F(2,148) = 4.0; P = 0.02] were significant with limb truncal tardive dyskinesia. Allelic/genotypic (P = 0.004/P = 0.01) association of rs1076560 with negative scale of PANSS in tardive dyskinesia-negative; diminished expression factor of PANSS in tardive dyskinesia-negative subcohort (allelic/genotypic P = 3.3 × 10/6.6 × 10) and tardive dyskinesia cohorts (P = 0.003/0.002); genotypic association (P = 0.05) with disorganised/concrete factor in tardive dyskinesia-positive subcohorts were observed by regression analysis using gPLINKv2.050. Further allelic/genotypic (P = 0.02) association of rs4680 with depressed factor of PANSS in tardive dyskinesia cohort was observed. Allelic/genotypic association of rs1076560 with abstraction and mental flexibilityaccuracy (P = 0.03/0.04), abstraction and mental flexibilityefficiency (P = 0.01/0.02); allelic association with spatial abilityprocessing speed (P = 0.03), emotionefficiency (P = 0.05); and with spatial abilityefficiency (genotypic, P = 0.05) in healthy controls and allelic association of rs4680 with emotionefficiency in cases with schizophrenia (P = 0.04) were notable., Principal Conclusion: Dopaminergic genes seem to contribute to tardive dyskinesia and cognition warranting replication.

Background: Dopamine-β-hydroxylase (DBH, EC 1.14.17.1), which converts dopamine to norepinephrine, is a candidate gene in neuropsychiatric diseases., Aim: To assess the effect of regulatory variants in DBH on schizophrenia and its endophenotypes -cognition and tardive dyskinesia., Methods: We tested association of functional variants 19bp Ins/Del , rs1989787 and rs1611115 in DBH with i) schizophrenia (1236 cases, 1136 controls), ii) tardive dyskinesia (83 positive, 162 negative) and iii) performance functions of cognition (357 cases, 306 controls) estimated by the Penn Computerized Neurocognitive Battery., Results: A modest haplotypic ( Ins -C; 19bp Ins/Del - rs1989787 C>T; p =0.04) association was observed with schizophrenia. We observed ~39% reduction in activity of 19bp Del allele on luciferase assay. Analysis of covariance revealed interactions of tardive dyskinesia status and: i) 19bp Ins/Del (genotypic, p =0.04) and ii) rs1989787 and rs1611115 (combined genotypic, p =0.004) on Abnormal Involuntary Movement Scale total score. Association of rs1611115 with positive and negative syndrome scale (PANSS) total score ( p =0.05) and allelic/genotypic association with lower positive ( p =0.03/0.04), general psychopathology ( p =0.01/0.01) PANSS scales in tardive dyskinesia-positive; and allelic/genotypic ( p =0.02/0.05) with higher score of depressive factors in tardive dyskinesia-negative subgroups were observed. Analysis of covariance with continuous variable of cognition showed interaction of health status with: i) rs1989787 on accuracy and efficiency ( p =0.03) of abstraction and mental flexibility; ii) rs1611115 on accuracy of working memory and emotion ( p =0.05); iii) 19bp Ins/Del on processing speed of emotion ( p =0.03). Allelic/genotypic association of rs1989787 with spatial ability ( p =0.02-0.05) among healthy controls; association of rs1611115 with Global Assessment Scale scores in the past month ( p =0.05) among schizophrenia subjects of cognition cohort was also observed., Conclusions: With modest genotype-phenotype correlations available for DBH variants, personalized treatment regimens based on DBH activity for ameliorating tardive dyskinesia and cognitive symptoms may be plausible.

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics. [ABSTRACT FROM AUTHOR]