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Population and family based association study on TPH1, TPH2 and ITGB3 genes indicate serotonergic system involvement in autism spectrum disorder Asem Surindro.

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Presentation on theme: "Population and family based association study on TPH1, TPH2 and ITGB3 genes indicate serotonergic system involvement in autism spectrum disorder Asem Surindro."— Presentation transcript:

1 Population and family based association study on TPH1, TPH2 and ITGB3 genes indicate serotonergic system involvement in autism spectrum disorder Asem Surindro Singh, Ph. D. Email : asemsuren @ gmail. com

2 ASD: childhood onset, genetic, neurodevelopmental disorder. (autism, asperger’s syndrom, PDD-NOS) Behaviorally defined 1.Lack of social interaction 2.Lack of communication 3.Restricted, repetitive behaviors and interests. Introduction Cerebral Cortex Basal Ganglia Corpus Callosum Cerebellum Brain stem Hippocampus Amygdala Pic: Jacob Bartnett Figure 1. Parts of brain affected by autism

3 High Prevalence: 1 in 68 children, (CDC, 2014). Concordance: 3 - 8% (dizygotic twins) and 69 – 95% (monozygotic twins) (Dawson G, 2008). Serotonin system abnormality in ASD: Brain and peripheral Serotonergic system: TPH1, TPH2, SLC6A4, SLC18A2, ITGB3. Serotonin abnormality: Synthesis, degradation, transport. Candidate gene association studies. Prevalence and cure: Urgently needed, pathophysiology unclear. Present study: TPH1, TPH2 and ITGB3 genes Two approaches: genetic association & gene-gene interaction analysis.

4 Figure 2. Diagrammatic representation of TPH1 showing the location of the investigated SNPs.

5 Figure 3. Diagrammatic representation of TPH2 showing the location of the investigated SNPs. Singh AS et al., PROG NEURO-PSYCHOPH, 2014

6 Figure 4. Diagrammatic representation of ITGB3 showing the location of the investigated SNPs. Singh AS et al., PROG NEURO-PSYCHOPH, 2014

7 Study Designs Blood collection Recruitment of subjects WBC separation DNA extraction Genetic association studies Approval of human ethics committee Genotyping analysis Gene-gene interaction analysis Bioinformatics analysis

8 Results in brief Table 1. Genotypic and allelic frequencies of ITGB3 and TPH2 Markers SNP IDStudy groupGenotypic frequency Allelic frequency HWE χ 2 p_ value ITGB3 rs15908CCCAAACA Case (n = 139)0.200.580.230.480.523.7400.053 Parent (n = 260)0.220.480.310.450.550.4130.520 Control (n = 165)0.240.560.210.520.482.1120.146 rs5918TTTCCCTC Case (n = 139)0.760.230.010.870.130.0430.834 Parent (n = 260)0.810.180.010.900.100.1480.700 Control (n = 163)0.760.230.010.870.130.1410.707 TPH2 rs4570625GGGTTTGT Case (n = 136)0.560.320.130.720.286.8920.008 Parent (n = 254)0.480.450.070.710.292.0680.150 Control (n = 129)0.570.360.070.750.250.2990.584 rs11179000AAATTTAT Case (n = 136)0.460.380.150.650.353.4160.064 Parent (n = 252)0.450.440.110.670.330.0990.752 Control (n = 131)0.440.450.110.660.340.0000.998 rs11179001GGGAAAGA Case (n = 136)0.680.300.030.820.180.0090.923 Parent (n = 252)0.710.250.040.840.162.2080.137 Control (n = 130)0.680.300.020.830.170.2560.612 rs4290270TTTAAATA Case (n = 132)0.330.460.200.560.440.5400.462 Parent (n = 245)0.310.480.210.550.450.2010.653 Control (n = 125)0.310.480.210.550.450.1400.707 rs7305115GGGAAAGA Case (n = 131)0.330.440.240.550.452.0870.148 Parent (n = 243)0.290.510.210.540.460.0710.788 Control (n = 159)0.250.510.240.510.490.0400.841

9 Table 2. Population wise data on the allele frequencies obtained from the HapMap dbSNP database and present study population from India Populati on TPH2ITGB3 rs4570625rs11179000rs11179001rs7305115rs4290270rs15908rs5918 GTATGAAGATCACT ASW0.6750.325NA 0.8680.1320.3600.640NA 0.3420.6580.1230.877 CEU0.7920.2080.7840.2160.9120.0880.3570.6430.2850.7150.3360.6640.1370.863 CHB0.4820.5180.4880.5120.8360.1640.4780.5220.5110.4890.5540.4560.0070.993 CHD0.4450.555NA 0.8390.1610.5830.417NA 0.6280.3720.0050.995 GIH0.7820.218NA 0.8510.1490.4600.540NA 0.4310.5690.0890.911 JPT0.5040.4960.4560.5440.8940.1060.4340.5660.4110.5890.5040.4960.0110.989 LWK0.5600.440NA 0.8730.1270.5140.486NA 0.5450.4550.1450.855 MEX0.6750.325NA 0.8360.1640.5090.491NA 0.3790.6210.1120.888 MKK0.5800.420NA 0.9390.0610.4780.522NA 0.6410.3590.1730.827 TSI0.7500.250NA 0.9110.0890.4750.525NA 0.4260.5740.1620.838 YRI0.6190.3810.5480.4520.8940.1060.3370.6630.5870.4130.4930.5070.1280.872 Study from INDIA 0.7500.2500.6600.3400.8300.1700.5500.4500.5100.4900.5200.4800.1300.870

10 Figure 5. Linkage analysis.

11 Figure 6. Multifactor dimensionality reduction test for case control

12 Marker combinationHRLRM (Fix P) TNTT rs4537731-rs2111065831678837.1 (0.026) rs623580-rs104886828051487525.5 (0.043) rs623580- rs45706255430719331.0 (0.024) rs623580- rs42902707847507822.4 (0.050) rs623580-rs1799913- rs45706256935568852.7 (0.026) rs623580- rs1799913- rs42902706932579045.7 (0.041) Table 3. MDR-phenomics analysis for TPH1 and TPH2 interaction using all trio families

13 Figure 7. Radial diagram showing genetic interaction pattern between the SNPs of the genes.

14 Figure 8. Bioinformatic analysis for protein-protein interaction

15 Interacting ProteinsText mining score SLC6A4 and TPH10.956 TPH2 and SLC6A40.889 HTR2A and TPH20.908 HTR2A and TPH10.963 HTR2A and SLC6A40.926 ITGB3 and SLC6A40.960 Table 4. Interacting proteins with the text mining scores resulted by online database resource Search Tool “ STRING ”

16 Table 5. Transcription factor and transcription factor binding site changes due to single nucleotide polymorphism SNP IDAllelesTFB sitesTFScore rs4570625GTAGAATA ←CdxA85.7 TAATTATA →CdxA98.6 TATAATA ←CdxA91.4 TATAATA →CdxA91.4 rs11179000A ACACGTGT → USF94.1 ACACGTGT ←USF94.1 GTACACGTGTTG → N-Myc90.8 TGTACACGTGTTGA ← USF88.2 TGTACACGTGTTGA → USF88.2 GTACACGTGTTG ← N-Myc87.6 GTACACGTGTTG → c-Myc86.8 GTACACGTGTTG ← MyoD86.0 TNA rs11179001A ACTGGAAGCA → c-Ets-90.2 G ACTGGAAGCG → c-Ets-89.2 ACTGGAAGCG → NRF-286.0

17 LD variation pattern was observed between the SNPs of case, control and parents. Pair-wise haplotype analysis reveal over-transmission ofTPH1. Pair-wise haplotype analysis showed under-expression of TPH2. MDR and MDRP showed significant interaction of TPH1 & TPH2 Indirect interaction of TPH1,TPH2 and ITGB3 was shown by bioinformatic analysis; and the SNP markers were shown to have functional (from low to moderate) role in gene regulation. Summary of the result

18  The present study using genetic association and gene-gene interaction analyses of TPH1, TPH2 and ITGB3 variants support the serotonergic abnormality in ASD.  The three genes are likely involve in the etiology of the disorder.  However further studies using cellular and animal models are required to validate the finding which may provide some important information in the disease pathophysiology and in the future therapeutic development of ASD. Conclusion

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