Prachi Semwal

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resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807).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.

Family-based association studies of monoaminergic gene polymorphisms among north indians with schizophrenia

Associations between schizophrenia and four candidate genes were tested among Indian patients with schizophrenia and their parents (DSM-IV criteria, n = 179 families). Polymorphisms within the genes encoding the serotonin 2A receptor (HT2A), tryptophan hydroxylase (TPH), catechol-O-methyl transferase (COMT) and dopamine transporter (DAT) were thus investigated. Two polymorphisms each were analyzed at HT2A and TPH, enabling haplotype-based analyses using the transmission disequilibrium test (TDT) for these genes. No significant associations were detected. Pooled analysis of samples like ours may be necessary to definitively exclude putative allelic associations at these loci.

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.

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.

Clinical and genetic correlates of severity in schizophrenia in India: An ordinal logistic regression approach

Genetic association studies of schizophrenia typically utilize diagnostic status as the trait of interest. Among Indian schizophrenia (SZ) participants, we evaluated genetic associations (selected single nucleotide polymorphisms (SNPs) associated with SZ) with selected indices of severity and symptom pattern. Ordinal logistic regression enabled us to analyze variables with multiple categories as outcome variables, while incorporating key demographic variables; this form of analysis may be useful in future genetic association studies. No significant associations were detected following corrections for multiple comparisons.

Replication Study Of Gwas And Other Strongly Associated Markers From Chromosome 6 In North Indian Population

Background Schizophrenia is a polygenic neuropsychiatric disorder wherein specific molecular or phenotypic markers have not been reported, with several promising findings but inconsistent replication. Nevertheless, different markers from chromosome 6, discussed repeatedly and reinforced by GWAS findings, remain the most promising leads. The present study was carried out to replicate the important GWAS findings (p Methods Schizophrenia cases (n=1035) and matched healthy controls (n=1035) were recruited at PGIMER-Dr.R.M.L. hospital. Controls included age and gender matched psychiatrically healthy adults and cord blood samples. Using Sequenome platform, 26 markers were evaluated. In a subset of the samples (n=173 cases; n=87 controls), 8 different cognitive domains were evaluated using the UPenn Computerized Neuropsychological Battery, for the markers. Results Three markers namely rs2064430 (p=0.04, OR= 1.14, CI=1.01-1.3, AHI), rs6932590 (p=0.05, OR= 0.85, CI=0.73-1.00, intergenic), rs6916921 (p=0.05,OR=1.19, CI=1.00-1.43, NFKBIL1) showed modest association to DSM IV schizophrenia diagnosis under allelic test of association while rs3130615 and rs6916394 showed genotypic (p=0.04, p=0.02) and recessive association (p=0.01, 0.05) but none withstood Bonferroni correction. The most significant 2 marker haplotype using PLINK sliding window came from four regions: 1) intergenic region -rs6932590|rs3800318 (TA, p=0.02) 2) HLADQA1 region- rs377763|rs9273012 (GA, p=0.04) and 3) TNF region- rs1800610|rs986475 (CC, p=0.03) 4) MICB region- rs3130615| rs2516489 (CG, p=0.04). Significant association was observed among cases for rs377763 (p = 1.54*10-6) with ‘Sensorimotor functioning’ domain of the battery. Discussion The present study, although reaffirms association of a few chromosome 6 markers to schizophrenia in this ethnically distinct North Indian population; was of far lower magnitude than p=10-8 seen in initial GWAS findings.