Presence of platelet hyperserotonemia and effective amelioration of behavioral dysfunctions by selective serotonin reuptake inhibitors (SSRI) in autism spectrum disorders (ASD) indicate that irregularities in serotonin (5-HT) reuptake and its homeostasis could be the basis of behavioral impairments in ASD patients. SLC6A4, the gene encoding serotonin transporter (SERT) is considered as a potential susceptibility gene for ASD, since it is a quantitative trait locus for blood 5-HT levels. Three functional polymorphisms, 5-HTTLPR, STin2 and 3'UTR-SNP of SLC6A4 are extensively studied for possible association with the disorder, with inconclusive outcome. In the present study, we investigated association of these polymorphisms with platelet 5-HT content and symptoms severity as revealed by childhood autism rating scale in ASD children from an Indian population. Higher 5-HT level observed in ASD was highly significant in children with heterozygous and homozygous genotypes comprising of minor alleles of the markers. Quantitative transmission disequilibrium test demonstrated significant genetic effect of STin2 allele as well as STin2/3'UTR-SNP and 5-HTTLPR/3'UTR-SNP haplotypes on 5-HT levels, but no direct association with overall CARS score and ASD phenotype. Significant genetic effect of the markers on specific behavioral phenotypes was observed for various sub-phenotypes of CARS in quantitative trait analysis. Even though the 5-HT level was not associated with severity of behavioral CARS score, a significant negative relationship was observed for 5-HT levels and level and consistency of intellectual response and general impression in ASD children. Population-based study revealed higher distribution of the haplotype 10/G of STin2/3'UTR-SNP in male controls, suggesting protective effect of this haplotype in male cases. Overall results of the study suggest that SLC6A4 markers have specific genetic effect on individual ASD behavioral attributes, might be through the modulation of 5-HT content.
Keywords: Childhood autism rating scale; Hyperserotonemia; Quantitative transmission disequilibrium test; Serotonin transporter; Transmission disequilibrium.
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