Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indian population

- ITGB3 SNP, rs5918 shows significant paternal allele transmission to male probands.
- Positive association of TPH2 haplotypes with ASD and autism in Indian population.
- Interaction between ITGB3 and TPH2 markers increases the risk towards ASD/autism.
- First study on gene-gene interaction between TPH2 and ITGB3 in ASD/autism.
- Insilico functional analysis support genetic association and interaction results.

BackgroundSerotoninergic dysfunction leads to neurodevelopmental abnormalities and behavioral impairments. Platelet hyperserotoninemia is reported as the best identified endophenotype for autism spectrum disorders. Therefore, in the present study we investigate the association of TPH2, the rate limiting enzyme in 5-HT biosynthesis and ITGB3, a serotonin quantitative trait locus with ASD in the Indian population.MethodsPopulation and family-based genetic association and gene-gene interaction analyses were performed to evaluate the role of ITGB3 and TPH2 markers in ASD etiology.ResultsAssociation tests using ITGB3 markers revealed significant paternal overtransmission of T allele of rs5918 to male probands. Interestingly for TPH2, we observed significant overrepresentation of A-A (rs11179000-rs4290270), G-A (rs4570625-rs4290270), G-G-A (rs4570625-rs11179001-rs4290270) and A-G-A (rs11179000-rs11179001-rs4290270) haplotypes in the controls and maternal preferential transmission of A-A (rs11179001-rs7305115), T-A-A (rs4570625-rs11179001-rs7305115) and T-A-A (rs11179000-rs11179001-rs7305115) and nontransmission of G-G-A (rs4570625-rs11179001-rs7305115) haplotypes to the affected offspring. Moreover, interaction of ITGB3 marker, rs15908 with TPH2 markers was found to be significant and influenced by the sex of the probands. Predicted individual risk, which varied from very mild to moderate, supports combined effect of these markers in ASD.ConclusionOverall results of the present study indicate likely involvement of ITGB3 and TPH2 in the pathophysiology of ASD in the Indian population.