Smita N. Deshpande

Evaluation of a Susceptibility Gene for Schizophrenia: Genotype Based Meta-Analysis of RGS4 Polymorphisms from Thirteen Independent Samples

BACKGROUND Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. METHODS In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). RESULTS The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. CONCLUSIONS Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Molecular genetics of schizophrenia: past, present and future

Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance which is also governed by non-genetic factors. Candidate genes identified on the basis of biochemical and pharmacological evidence are being tested for linkage and association studies. Neurotransmitters, especially dopamine and serotonin have been widely implicated in its etiology. Genome scan of all human chromosomes with closely spaced polymorphic markers is being used for linkage studies. The completion and availability of the first draft of Human Genome Sequence has provided a treasure-trove that can be utilized to gain insight into the so far inaccessible regions of the human genome. Significant technological advances for identification of single nucleotide polymorphisms (SNPs) and use of microarrays have further strengthened research methodologies for genetic analysis of complex traits. In this review, we summarize the evolution of schizophrenia genetics from the past to the present, current trends and future direction of research.

Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects : III. lack of association of CYP3A4 and CYP2D6 gene polymorphisms

Tardive dyskinesia is a severe debilitating movement disorder characterized by choreoathetotic movements developing in one-fifth of the patients with schizophrenia. In this study we have investigated the significance of CYP3A4*1B and CYP2D6*4 polymorphisms in TD susceptibility among chronic schizophrenia patients (n = 335) from north India. Tardive dyskinesia was diagnosed in approximately 29% (96/335) of these patients. No significant association of either of the two SNPs with TD (CYP3A4*1B chi2 = 0. 308, df = 1, p = 0.579; CYP2D6*4 chi2 = 0.006, df = 1, p = 0.935) was observed. However a trend towards increased severity of TD in patients heterozygous for the CYP2D6*4 mutation was observed.

Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication.

Objectives To investigate the role of genes encoding regulators of G protein signaling in early therapeutic response to antipsychotic drugs and in susceptibility to drug-induced extrapyramidal symptoms. As regulators of G protein signaling and regulators of G protein signaling-like proteins play a pivotal role in dopamine receptor signaling, genetically based, functional variation could contribute to interindividual variability in therapeutic and adverse effects. Methods Consecutively hospitalized, psychotic patients with Diagnostic and Statistical Manual of Mental Disorder-IV schizophrenia (n=121) were included in the study if they received treatment with typical antipsychotic medication (n=72) or typical antipsychotic drugs and risperidone (n=49) for at least 2 weeks. Clinical state and adverse effects were rated at baseline and after 2 weeks. Twenty-four single nucleotide polymorphisms were genotyped in five regulators of G protein signaling genes. Results None of the single nucleotide polymorphisms were related to clinical response to antipsychotic treatment at 2 weeks. Five out of six single nucleotide polymorphisms within or flanking the RGS2 gene were nominally associated with development or worsening of parkinsonian symptoms (PARK+) as measured by the Simpson Angus Scale, one of them after correction for multiple testing (rs4606, P=0.002). A GCCTG haplotype encompassing tagging single nucleotide polymorphisms within and flanking RGS2 was significantly overrepresented among PARK+ compared with PARK− patients (0.23 vs. 0.08, P=0.003). A second, ‘protective’, GTGCA haplotype was significantly overrepresented in PARK− patients (0.13 vs. 0.30, P=0.009). Both haplotype associations survive correction for multiple testing. Conclusions Subject to replication, these findings suggest that genetic variation in the RGS2 gene is associated with susceptibility to extrapyramidal symptoms induced by antipsychotic drugs.

Culture and Hallucinations: Overview and Future Directions

A number of studies have explored hallucinations as complex experiences involving interactions between psychological, biological, and environmental factors and mechanisms. Nevertheless, relatively little attention has focused on the role of culture in shaping hallucinations. This article reviews the published research, drawing on the expertise of both anthropologists and psychologists. We argue that the extant body of work suggests that culture does indeed have a significant impact on the experience, understanding, and labeling of hallucinations and that there may be important theoretical and clinical consequences of that observation. We find that culture can affect what is identified as a hallucination, that there are different patterns of hallucination among the clinical and nonclinical populations, that hallucinations are often culturally meaningful, that hallucinations occur at different rates in different settings; that culture affects the meaning and characteristics of hallucinations associated with psychosis, and that the cultural variations of psychotic hallucinations may have implications for the clinical outcome of those who struggle with psychosis. We conclude that a clinician should never assume that the mere report of what seems to be a hallucination is necessarily a symptom of pathology and that the patient’s cultural background needs to be taken into account when assessing and treating hallucinations.

Candidate gene polymorphisms among North Indians and their association with schizophrenia in a case-control study

Knowledge of candidate gene polymorphisms in a population is useful for a variety of gene-disease association studies, particularly for some complex traits. A number of candidate genes, a majority of them from the monoaminergic pathway in the brain, have been very popular in association studies with schizophrenia, a neuropsychiatric disorder. In this study diallelic/multiallelic polymorphisms in some dopaminergic, serotonergic and membrane-phospholipid-related genes have been evaluated in a control population recruited from North India. Association, if any, of these allelic variants with schizopherenia has been tested using a case-control approach. The case data have been taken from our published family-based association studies in schizophrenia. Of the eight genes tested in this study, association with schizophrenia was observed for only two gene polymorphisms, one in the promoter region of the serotonin 2A receptor gene and the other in the tryptophan hydroxylase gene. One new allele for the dopamine transporter gene (with eight repeats, 570-bp size), not reported in any population so far, has been identified in one individual in our sample. The data generated in this study, besides providing a normative background for various disease association studies, are a significant contribution to the population-specific genome database, a currently growing requirement.

Association studies of cytosolic phospholipase A2 polymorphisms and schizophrenia among two independent family-based samples.

An association between the cytosolic phospholipase A2 locus (cPLA2) and schizophrenia has been reported using two polymorphic DNA markers. In an attempt to replicate these results, two independent family-based samples were ascertained from the United States and India (86 and 159 families, respectively). No significant associations were detected in either sample.

Correlates of hallucinations in schizophrenia: A cross‐cultural evaluation

INTRODUCTION Demographic, clinical and familial factors may plausibly influence the manifestation of hallucinations. It is unclear if the pattern of the effects is similar in different environmental/cultural settings. AIMS To evaluate factors associated with hallucination from a demographic, clinical and familial perspective in two distinct cultural settings. METHODS Patients with a clinical diagnosis of schizophrenia (SZ) or schizoaffective disorder (SZA) were diagnosed systematically using DSM IV criteria. Two independent samples were recruited in India and USA using identical inclusion/exclusion criteria and assessment procedures (n=1287 patients total; 807 Indian and 480 US participants). The association of key demographic and clinical factors with hallucinations of different modalities was examined. To evaluate the impact of familial factors, we separately analyzed correlations among affected sibling pairs (ASPs, n=136, Indian; n=77, US). RESULTS The prevalence of different modalities of hallucinations differed in the Indian and US samples, though the rank order of frequency was similar. The pattern of associations between selected variables and the risk of hallucinations was different across cultures, except for some correlations with indices of severity. No significant concordance was observed among the ASPs after correcting for multiple comparisons. CONCLUSIONS The factors associated with hallucinations vary across environments. Our results are consistent with a multi-factorial etiology of psychopathology, but re-direct attention to endophenotypic features in the causal chain that precede the symptoms themselves.

Adjunctive cognitive remediation for schizophrenia using yoga: an open, non-randomized trial

Background: Yoga therapy (YT) improves cognitive function in healthy individuals, but its impact on cognitive function among persons with schizophrenia (SZ) has not been investigated. Objective: To evaluate the adjunctive YT for cognitive domains impaired in SZ. Methods: Patients with SZ received YT or treatment as usual (TAU; n = 65, n = 23, respectively). Accuracy and speed for seven cognitive domains were assessed using a computerised neurocognitive battery (CNB), thus minimising observer bias. Separately, YT was evaluated among patients with bipolar I disorder (n = 40), major depressive disorder (n = 37) and cardiology outpatients (n = 68). All patients also received routine pharmacotherapy. Patients were not randomised to YT or TAU. Results: In comparison with the SZ/TAU group, the SZ/YT group showed significantly greater improvement with regard to measures of attention following corrections for multiple comparisons; the changes were more prominent among the men. In the other diagnostic groups, differing patterns of improvements were noted with small-to-medium effect sizes. Conclusions: Our initial analyses suggest nominally significant improvement in cognitive function in SZ with adjunctive therapies such as YT. The magnitude of the change varies by cognitive domain and may also vary by diagnostic group.

Genetic correlates of olanzapine-induced weight gain in schizophrenia subjects from north India: role of metabolic pathway genes

AIM Olanzapine is an efficacious drug often used as a first-line medication in the treatment for schizophrenia. However, weight gain is a notable adverse drug reaction of this medication in a proportion of patients and a major cause of noncompliance. Several hypotheses, including a contribution from hormonal, physiological and environmental factors, have been postulated. In this study, we aimed to analyze a possible association of genetic polymorphisms at four important candidate genes involved in appetite regulation and antipsychotic-induced metabolic syndrome with olanzapine-induced weight gain. MATERIALS & METHODS A total of 154 schizophrenia subjects were recruited in a systematic, 6-week, open-label trial of olanzapine. We investigated the contribution of 14 polymorphisms from four genes, namely, leptin, lipoprotein lipase, tri-acyl-glycerol lipase and citrate lyase using a binary logistic regression analysis towards olanzapine-induced weight gain. RESULTS rs 4731426 C/G SNP, a variant in the leptin gene, was moderately associated with median weight gain (Delta weight(m); [p = 0.05; OR: 2.2; 95% CI: 0.99-4.90]) and significantly associated with extreme weight gain (Delta weight(e) [p = 0.019; OR: 11.43; 95% CI: 1.49-87.55]) when average drug dose was included in a regression model. Using in silico analysis, we found that this associated intronic SNP in the leptin gene alters the binding of zinc finger 5, a transcription factor. CONCLUSION The leptin gene may be a promising candidate for olanzapine-induced weight gain. As the associations are modest, replicate studies are warranted. This approach may facilitate rationalized drug regimens.