Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

Abstract

Serotonin (5-hydroxytryptamine (5-HT)) transporter (SLC6A4) is known to influence mood, emotion, cognition and efficacy of antidepressants, particularly that of selective serotonin reuptake inhibitors. Atypical antipsychotics exert their effects partially through serotinergic systems, and hence, variation in 5-HT uptake may affect antipsychotic action mediated through the serotinergic system. Therefore, investigating the role of SLC6A4 as a risk factor for developing schizophrenia and treatment response had been a point of concern for many investigators, but with variable outcome. In this study, we examined the genetic roles of five polymorphisms of SLC6A4, including those of the widely studied 44 base pair variable number of tandem repeat (VNTR) in the promoter region of SLC6A4 (the serotonin transporter gene-linked polymorphic region: 5HTTLPR) and a VNTR polymorphism (STin2) in the second intron, in schizophrenia and its influence on the severity of symptoms in a South Indian population from Kerala, comprising 586 individuals. We detected significant allelic and genotypic associations with rs2066713 (both allelic and genotypic P-value o0.001), 5HTTLPR (allelic P-value¼0.008 and genotypic P-value¼0.03) and STin2 polymorphisms (allelic P-value¼0.001 and genotypic P-value¼0.002). A haplotype linking these three risk alleles, 5HTTLPR/ S-rs2066713/C-STin2/12-repeat (P-value¼0.0059), was also significantly associated with disease in our population. Patients with STin2 12-repeat homozygotes showed a greater severity of blunted effect symptom. These results suggest a strong role of SLC6A4 in schizophrenia, possibly with a specific behavioral endophenotype in a South Indian population. Keywords: case-control; SLC6A4; schizophrenia; South India; symptom profile INTRODUCTION Schizophrenia is a common and complex psychiatric disorder, with proven genetic causes. Research to unravel the genetic basis of schizophrenia has revealed several molecules, including those involved in dopamine and serotonin neurotransmitter systems for the past few decades. Serotonin (5-hydroxytryptamine (5-HT)) hypothesis of schizophrenia has been reanalyzed with the effectiveness of clozapine, the best known atypical antipsychotic drug, 1 as an antagonist for several 5-HT receptors. 2,3 Moreover, 5-HT has been shown to regulate the development of the central nervous system. As the 5-HT transporter (5-HTT) regulates the 5-HT system, 4 alterations in the function of this protein could be involved in the development of schizophrenia. 5 The serotonin transporter (SLC6A4) gene spanning 37.8 kb is located on chromosome 17q11.2, 6,7 and has 14 exons encoding a protein of 630 amino acids. 8 SLC6A4 has received attention as a candidate in schizophrenia and mood disorders, owing to its influence on mood, emotion, cognition and also because 5-HTT is the principal site of action for some antidepressants, particularly for the selective

Evaluation of psychiatric and genetic risk factors among primary relatives of suicide completers in Delhi NCR region, India

“…Studies report that the short(S) allele is associated with depression and suicide (Kiyohara and Yoshimasu, 2010;Neves et al, 2008;Wasserman et al, 2007) whereas, some reports do not establish risk with suicidal behavior (Zalsman et al, 2001, Shen et al, 2004. As per frequency data S allele is relatively high in Indian population, as reported in an earlier study of Vijayan et al, (2009) and ranges between 0.50 and 0.58 in schizophrenia controls and case samples from south India respectively. Experimental observations show low promoter activity in short allele of 5-HTTLPR, resulting in a decreased gene expression and reduced serotonin uptake at synapses (Heils et al,1997) and in prefrontal cortical regions of suicide completers (Austin et al, 2002).…”

High frequency of known copy number abnormalities and maternal duplication 15q11-q13 in patients with combined schizophrenia and epilepsy

“…This duplication is quite common, but its phenotypic significance is not clear [47]. SLC6A4 encodes a protein involved in the transport of serotonin and there is a report of genetic association with schizophrenia [48]. Additional findings of unknown significance in schizophrenia plus epilepsy samples are listed in Table 3.…”

Association and interaction analyses of 5-HT3 receptor and serotonin transporter genes with alcohol, cocaine, and nicotine dependence using the SAGE data

“…As a tag SNP located in the alternative splicing region of SLC6A4 involving noncoding exons 1A and 1B, it is likely to regulate expression of the gene in humans, because exon 1B is surrounded by several consensus sites for transcription factors AP-1, AP-2, CREB/ATF, and NF-κB (Bradley and Blakely 1997). Rs2066713 was reported to be associated with schizophrenia in a South Indian population (Vijayan et al 2009) and with autism in Caucasian samples (Ma et al 2010). On the haplotypic level, two SNPs located in the 5 -region of HTR3B (i.e., rs3891484 and rs3758987) and three SNPs located in the 3 -region of HTR3A (i.e., rs7118530, rs12221649, and rs2085421) are associated with AD in the AA sample and FTND in the EA sample, respectively.…”