Meera Purushottam

Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment

AIM We investigated the catechol-O-methyltrasferase (COMT) gene, which is a strong functional and positional candidate gene for schizophrenia and therapeutic response to antipsychotic medication. MATERIALS & METHODS Single-locus as well as detailed haplotype-based association analysis of the COMT gene with schizophrenia and antipsychotic treatment response was carried out using seven COMT polymorphisms in 398 schizophrenia patients and 241 healthy individuals from a homogeneous south Indian population. Further responsiveness to risperidone treatment was assessed in 117 schizophrenia patients using Clinical Global Impressions (CGI). A total of 69 patients with a CGI score of 2 or less met the criteria of good responders and 48 were patients who continued to have a score of 3 and above and were classified as poor responders to risperidone treatment. RESULTS The association of SNP rs4680 with schizophrenia did not remain significant after adjusting for multiple testing. Haplotype analysis showed highly significant association of seven COMT marker haplotypes with schizophrenia (CLUMP T4 p-value = 0.0001). Our results also demonstrated initial significant allelic associations of two SNPs with drug response (rs4633: chi(2) = 4.36, p-value = 0.036, OR: 1.80, 95% CI: 1.03-3.15; and rs4680: chi(2) = 4.02, p-value = 0.044, OR: 1.76, 95% CI: 1.01-3.06) before multiple correction. We employed two-marker sliding window analysis for haplotype association and observed a significant association of markers located between intron 1 and intron 2 (rs737865, rs6269: CLUMP T4 p-value = 0.021); and in exon 4 (rs4818, rs4680: CLUMP T4 p-value = 0.028) with drug response. CONCLUSION The present study thus indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients. However, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies.

Genetic susceptibility to schizophrenia: role of dopaminergic pathway gene polymorphisms

AIM We investigated 16 polymorphisms from three genes, dopamine receptor D2 (DRD2), catechol-O-methyl transferase (COMT) and brain derived neurotrophic factor (BDNF), which are involved in the dopaminergic pathways, and have been reported to be associated with susceptibility to schizophrenia and response to antipsychotic therapy. MATERIALS & METHODS Single-locus association analyses of these polymorphisms were carried out in 254 patients with schizophrenia and 225 controls, all of southern Indian origin. Additionally, multifactor-dimensionality reduction analysis was performed in 422 samples (243 cases and 179 controls) to examine the gene-gene interactions and to identify combinations of multilocus genotypes associated with either high or low risk for the disease. RESULTS Our results demonstrated initial significant associations of two SNPs for DRD2 (rs11608185, genotype: chi(2) = 6.29, p-value = 0.043; rs6275, genotype: chi(2) = 8.91, p-value = 0.011), and one SNP in the COMT gene (rs4680, genotype: chi(2) = 6.67, p-value = 0.035 and allele: chi(2) = 4.75, p-value = 0.029; odds ratio: 1.33, 95% confidence interval: 1.02-1.73), but not after correction for multiple comparisons indicating a weak association of individual markers of DRD2 and COMT with schizophrenia. Multifactor-dimensionality reduction analysis suggested a two locus model (rs6275/DRD2 and rs4680/COMT) as the best model for gene-gene interaction with 90% cross-validation consistency and 42.42% prediction error in predicting disease risk among schizophrenia patients. CONCLUSION The present study thus emphasizes the need for multigene interaction studies in complex disorders such as schizophrenia and to understand response to drug treatment, which could lead to a targeted and more effective treatment.

Gray matter volume deficits in spinocerebellar ataxia: An optimized voxel based morphometric study ☆

INTRODUCTION Spinocerebellar ataxias (SCA) are a group of autosomal dominant ataxias with varied clinical phenotypes. However there are no unique distinguishing features on routine neuroimaging among the various genetically defined SCAs. Voxel-based morphometry (VBM) provides an automated unbiased analysis of structural MRI scans and gives a comprehensive assessment of anatomical differences throughout the brain. OBJECTIVES The aims of this study were to (i) characterize the patterns of atrophy in SCA1, SCA2 and SCA3 using optimized VBM, (ii) demonstrate the characteristic anatomical differences in these genetically distinct SCA subtypes, and (iii) assess the relationship between morphometric measures and the CAG repeat lengths and other attributes of the disease. METHODS Thirty-one genetically confirmed patients suffering from SCA (SCA1 - 12, SCA2 - 9, and SCA3 - 10) were studied. High resolution T1-weighted 3-Dimensional Magnetic Resonance Images of 31 patients were analyzed using the optimized VBM procedure. RESULTS In all the three SCAs there was a significant loss of gray matter in both cerebellar hemispheres and vermis. Vermian atrophy was more pronounced in SCA3, while SCA1 and SCA2 had significant white matter atrophy. Pontine white matter atrophy was more pronounced in SCA2. In SCA1, the severity of ataxia strongly correlated with the degree of gray matter atrophy in cerebellar hemispheres. The duration of symptoms and lengths of CAG repeats had no correlation with the degree of atrophy. CONCLUSIONS This study showed that the different subtypes of SCAs may have morphometric differences in the cerebellum, brainstem and the supratentorial structures.

Cellular models to study bipolar disorder: a systematic review

BACKGROUND There is an emerging interest in the use of cellular models to study psychiatric disorders. We have systematically reviewed the application of cellular models to understand the biological basis of bipolar disorder (BD). METHOD Published scientific literature in MEDLINE, PsychINFO and SCOPUS databases were identified with the following search strategy: [(Lymphoblastoid OR Lymphoblast OR Fibroblast OR Pluripotent OR Olfactory epithelium OR Olfactory mucosa) AND (Bipolar disorder OR Lithium OR Valproate OR Mania)]. Studies were included if they had used cell cultures derived from BD patients. RESULTS There were 65 articles on lymphoblastoid cell lines, 14 articles on fibroblasts, 4 articles on olfactory neuronal epithelium (ONE) and 2 articles on neurons reprogrammed from induced pluripotent stem cell lines (IPSC). Several parameters have been studied, and the most replicated findings are abnormalities in calcium signaling, endoplasmic reticulum (ER) stress response, mitochondrial oxidative pathway, membrane ion channels, circadian system and apoptosis related genes. These, although present in basal state, seem to be accentuated in the presence of cellular stressors (e.g. oxidative stress--rotenone; ER stress--thapsigargin), and are often reversed with in-vitro lithium. CONCLUSION Cellular modeling has proven useful in BD, and potential pathways, especially in cellular resilience related mechanisms have been identified. These findings show consistency with other study designs (genome-wide association, brain-imaging, and post-mortem brain expression). ONE cells and IPSC reprogrammed neurons represent the next generation of cell models in BD. Future studies should focus on family-based study designs and combine cell models with deep sequencing and genetic manipulations.

Serotonergic candidate genes and puerperal psychosis: an association study.

Background Altered serotonergic function is implicated in the aetiology and pathogenesis of a host of psychiatric disorders, and structural variations/polymorphisms in genes encoding the serotonin transporter and various serotonin receptor subtypes are attractive candidates to investigate the biological component underlying these disorders. Specific phenotypic subtypes, that perhaps represent homogeneous forms of the disorder, may increase the power to detect genes in complex diseases. Objective We investigated regulatory and functional polymorphic DNA markers of serotonergic candidate genes using a case–control approach in puerperal psychosis and bipolar affective disorder probands. Methods We genotyped 320 female participants (104 puerperal psychosis probands, 102 bipolar disorder participants and 114 controls) at the serotonin transporter SERT (5-HTT) 5-HTTVNTR and 5-HTTLPR locus; serotonin receptor 2A (5-HT2A)-T102C and His452Tyr loci, the serotonin receptor 2C (5-HT2C)-Cys23Ser locus, and seven unrelated Alu polymorphic markers. Results We observed an association of the puerperal psychosis phenotype with the allele 10 of 5-HTTVNTR of SERT (P=0.004) and a modest association with the genotypic frequencies of the 5-HTTLPR (P=0.036). A nominal P value of 0.006 was observed with the S-10 haplotype in the PP group as compared with bipolar affective disorder probands. Significant association was observed with bipolar affective disorder phenotype with Tyr allele of the 5-HT2A His452Tyr gene polymorphism (P=0.00043) even after a conservative multiple test correction. No association was observed, however, with the 5-HT2A T102C locus, and the distribution of the other seven Alu markers did not differ between the groups. Conclusion The association between polymorphisms in serotonergic genes (SERT and 5-HT2A, 5-HT2C) suggests that these genetic factors can modulate vulnerability to puerperal psychosis in female bipolar participants.

Shortened telomere in unremitted schizophrenia

Telomere attrition has been noted in many neuropsychiatric and neurodegenerative syndromes, and may indicate a shared molecular pathology across conditions. We evaluated telomere length in subjects with remitted and unremitted schizophrenia and in control subjects.

DRD4 gene and obsessive compulsive disorder: Do symptom dimensions have specific genetic correlates?

INTRODUCTION The dopamine D4 receptor (DRD4) is a promising candidate gene in obsessive compulsive disorder (OCD). A 48-bp variable number of tandem repeats (VNTR) sequence in exon 3 has been studied previously, and alleles containing 2-11 repeats (2R-11R) have been identified. We investigated the association of DRD4 VNTR polymorphism with OCD and its relationship with various clinical parameters (age of onset, gender, family history, co-morbidity, factor-analyzed symptom dimensions and insight). METHODOLOGY One hundred and seventy three South Indian OCD patients (DSM-IV) recruited from a specialty OCD clinic were evaluated using the Yale-Brown obsessive compulsive scale (YBOCS), YBOCS item-11 for insight, Mini International Neuropsychiatric Interview (MINI) plus, tic disorder subsection of the MINI-KID and Clinical Global Impression scale. 201 healthy controls were evaluated using MINI plus. All subjects were genotyped for the DRD4 VNTR polymorphism. RESULTS Genotype frequencies did not deviate significantly from the Hardy-Weinberg equilibrium. Case-control association analysis revealed that the 7R allele frequency was significantly greater in OCD patients than controls. This difference was restricted to the women subsample when performing the gender sub-analysis. Among other clinical variables examined, factor 3 (symmetry) was associated with presence of 2R allele. Linear regression analysis confirmed the association of symmetry dimension with the 2R allele (Beta=0.23, t=2.96, p=0.004, CI=0.19-0.95). CONCLUSIONS Our data provides further evidence that DRD4 VNTR polymorphism is associated with OCD. Furthermore, the presence of the 2R allele was significantly associated with the symmetry dimension. This dimension may represent a more homogeneous subtype of OCD with a genetic etiology.

Phylogenetic analysis and selection pressures of 5-HT receptors in human and non-human primates: receptor of an ancient neurotransmitter.

Abstract Neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) an ancient neurotransmitter, involved in several neurophysiological and behavioral functions, acts by interacting with multiple receptors (5-HT1-5-HT7). Alterations in serotonergic signalling have also been implicated in various psychiatric disorders. The availability of the genome data of nonhuman primates permits comparative analysis of human 5-HT receptors with sequences of non-human primates to understand evolutionary divergence. We compared and analyzed serotonergic receptor sequences from human and non-human primates. Phylogenetic analysis by Maximum Likelihood (ML) method classified human and primate 5-HT receptors into six unique clusters. There was considerable conservation of 5-HT receptor sequences between human and non-human primates; however, a greater diversity at the sub-group level was observed. Compared to the other subgroups, larger multiplicity and expansion was seen within the 5-HT4 receptor subtype in both human and non-human primates. Analysis of non-synonymous and synonymous substitution ratios (Ka/Ks ratio) using the Nei-Gojobori method suggests that 5-HT receptor sequences have undergone negative (purifying) selection over the course of evolution in human, chimpanzee and rhesus monkey. Abnormal human and non-human primate psychopathalogy and behavior, in the context of these variations is discussed. Analysis of these 5-HT receptors in other species will help understand the molecular evolution of 5-HT receptors, and its possible influence on complex behaviors, and psychiatric disorders.

Spinocerebellar ataxias types 1, 2 and 3 : Age adjusted clinical severity of disease at presentation correlates with size of CAG repeat lengths

OBJECTIVE The objective of this study was to determine the correlation, if any, between the clinical rate of disease progression at presentation with the CAG repeat size in patients with spinocerebellar ataxias 1, 2 and 3 (SCA1, SCA2 and SCA3). METHODS The severity of ataxia was measured using the International Cooperative Ataxia Rating Scale (IARS) in 31 patients of SCA1 (mean+/-SD age: 35.1+/-12.6 years; age at onset (AAO): 29.9+/-10.7 years), 25 patients of SCA2 (age: 34.9+/-14.9 years; AAO: 29.7+/-14.0 years) and 15 patients of SCA3 (age: 40.9+/-8.6 years; AAO: 36.9+/-10.1). The rate of disease progression at presentation was measured by the age adjusted IARS (IARS/Age). For each SCA, correlations of AAO, raw scores of IARS, age adjusted IARS and duration adjusted IARS (IARS/Duration) with the CAG repeat size were determined. RESULTS The number of CAG repeats of the abnormal allele ranged from 42 to 67 in SCA1, 38 to 66 in SCA2, and 69 to 79 in SCA3. In all the three types of SCAs, there were significant inverse correlations of AAO with CAG repeat size (SCA1: r=-0.9, p<0.0001; SCA2: r=-0.7, p<0.0001; SCA3:-0.8, p=0.0003) and significant positive correlations of IARS/Age with CAG repeat size (SCA1: r=0.6, p=0.0015; SCA2: r=0.9, p<0.0001; SCA3:0.7, p=0.0057). However, the raw IARS scores and the duration adjusted IARS scores did not correlate significantly with the CAG repeat sizes. CONCLUSIONS These data suggest that the rate of clinical disease progression at presentation, especially in SCA2, is dependent on the CAG repeat size, and may commence linearly from birth.

Apolipoprotein E Polymorphism and Dementia: A Hospital-Based Study from Southern India

Background/Aims: To evaluate the ApoE gene polymorphism among patients with dementia from southern India. Methods: Persons with dementia attending a geriatric clinic in a hospital setting located in southern India and matched controls were recruited. All subjects were evaluated on standard assessments and were diagnosed according to the ICD-10; genotyping was done at the apolipoprotein E (ApoE) locus. Results: The study comprised 212 cases and 195 controls. The ApoE4 allele was significantly more prevalent in dementia (λ = 0.18 vs. λ = 0.07; p = 0.0018), especially in the Alzheimer’s disease subgroup (n = 137; λ = 0.21 vs. λ = 0.07; p < 0.001), with a trend in vascular dementia subtype (n = 31; λ = 0.17 vs. λ = 0.07) in comparison with the control group. ApoE4 carrier status did not differ between the other dementia group (n = 44) and controls (p > 0.20), or between the Alzheimer’s group and vascular dementia groups. Cognitive and functional deficits were not correlated to the presence ApoE4 polymorphism in the dementia group. Conclusion: The study confirmed the positive association of the ApoE4 polymorphism in dementia, both in the Alzheimer’s and vascular etiology subgroups. Influence of this polymorphism on various clinical phenotypes, including extent of cognitive and functional deficits, needs further evaluation.