Triptish Bhatia

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 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.

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.

Differing correlates for suicide attempts among patients with schizophrenia or schizoaffective disorder in India and USA.

BACKGROUND Suicide is one of the most common causes of death among persons with schizophrenia. Differing risk factors have been identified in published studies. The differences may have arisen because a uniform set of variables was not analyzed. Alternatively, the nature and effect of risk factors may vary in different settings. To test these possibilities, we investigated the same set of variables in two independent cross-national samples ascertained using identical protocols. METHODS Patients with schizophrenia or schizoaffective disorder (DSM IV criteria) were recruited in India (n=460) and the USA (n=424). RESULTS Consistent with earlier publications, a diagnosis of schizoaffective disorder, history of depression, pattern of symptoms and educational status were significantly associated with suicide attempts in the US sample. None of these variables were significantly associated in the Indian sample. CONCLUSIONS The impact of known risk factors for suicide attempts among patients with schizophrenia differs across ethnic groups.

II. Serotonin receptor gene polymorphisms and their association with tardive dyskinesia among schizophrenia patients from North India.

Department of Psychiatry, Dr. Ram Manohar Lohia Hospital, New Delhi 110 001, Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, Biometrics Division, Indian Agricultural Statistics Research Institute, New Delhi 110 012, India, Department of Psychiatry, University of Pittsburgh, PA 15213, USA and Department of Psychiatry, Hadassah-Hebrew University Medical Centre, Ein Karem, Jerusalem 91120, Israel. Sponsorships: This work is supported by Indo-Israel Grants # BT/IC-2/00/Smita/ 99; BT/IC-2/Israel/Deshpande/2002 and the Department of Biotechnology, Government of India, Grant # BT/PR2425/Med/13/089/2001.

Association study of schizophrenia among Indian families.

A putative association of schizophrenia with a Msc I restriction fragment length polymorphism at the dopamine D3 receptor gene locus (DRD3) was tested among Indian families, using haplotype relative risk analysis and the transmission disequilibrium test (n=66 families and 58 sets of transmissions, respectively). A significant association either with homozygosity or with allele 1 at the biallelic polymporphism could not be detected.

Association study of Neuregulin-1 gene polymorphisms in a north Indian schizophrenia sample

BACKGROUND Neuregulin-1 (NRG1) gene polymorphisms have been proposed as risk factors for several common disorders. Associations with cognitive variation have also been tested. With regard to schizophrenia (SZ) risk, studies of Caucasian ancestry samples indicate associations more consistently than East Asian samples, suggesting heterogeneity. To exploit the differences in linkage disequilibrium (LD) structure across ethnic groups, we conducted a SZ case-control study (that included cognitive evaluations) in a sample from the north Indian population. METHODS NRG1 variants (n=35 SNPs, three microsatellite markers) were initially analyzed among cases (DSM IV criteria, n=1007) and controls (n=1019, drawn from two groups) who were drawn from the same geographical region in North India. Nominally significant associations with SZ were next analyzed in relation to neurocognitive measures estimated with a computerized neurocognitive battery in a subset of the sample (n=116 cases, n=170 controls). RESULTS Three variants and one microsatellite showed allelic association with SZ (rs35753505, rs4733263, rs6994992, and microsatellite 420M9-1395, p≤0.05 uncorrected for multiple comparisons). A six marker haplotype 221121 (rs35753505-rs6994992-rs1354336-rs10093107-rs3924999-rs11780123) showed (p=0.0004) association after Bonferroni corrections. Regression analyses with the neurocognitive measures showed nominal (uncorrected) associations with emotion processing and attention at rs35753505 and rs6994992, respectively. CONCLUSIONS Suggestive associations with SZ and SZ-related neurocognitive measures were detected with two SNPs from the NRG1 promoter region in a north Indian cohort. The functional role of the alleles merits further investigation.

Association analysis of NOTCH 4 polymorphisms with schizophrenia among two independent family based samples.

The present study investigated polymorphisms of the NOTCH 4 gene in two independent samples from India and USA, consisting of patients with schizophrenia and their parents (n = 182, and n = 148 ‘trios,’ respectively). Five DNA markers, namely (GAAG)n, (TAA)n, SNP1, SNP2, and (CTG)n were evaluated. Transmission distortion, consistent with a modest association was detected among both samples. Additional association studies at this locus are warranted.

Motor function deficits in schizophrenia: an fMRI and VBM study

IntroductionTo investigate whether the motor functional alterations in schizophrenia (SZ) are also associated with structural changes in the related brain areas using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM).MethodsA sample of 14 right-handed SZ patients and 14 right-handed healthy control subjects matched for age, sex, and education were examined with structural high-resolution T1-weighted MRI; fMRI images were obtained during right index finger-tapping task in the same session.ResultsfMRI results showed reduced functional activation in the motor areas (contralateral precentral and postcentral gyrus) and ipsilateral cerebellum in SZ subjects as compared to healthy controls (n = 14). VBM analysis also revealed reduced grey matter in motor areas and white matter reduction in cerebellum of SZ subjects as compared to controls.ConclusionThe present study provides an evidence for a possible association between structural alterations in the motor cortex and disturbed functional activation in the motor areas in persons affected with SZ during a simple finger-tapping task.