Original Investigation

Human Genetics

, Volume 121, Issue 2, pp 243-256

First online:

Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels

  • Ana M. CoutinhoAffiliated withInstituto Gulbenkian de Ciência
  • , Inês SousaAffiliated withInstituto Gulbenkian de Ciência
  • , Madalena MartinsAffiliated withInstituto Gulbenkian de CiênciaInstituto Nacional de Saúde Dr. Ricardo Jorge
  • , Catarina CorreiaAffiliated withInstituto Gulbenkian de CiênciaInstituto Nacional de Saúde Dr. Ricardo Jorge
  • , Teresa MorgadinhoAffiliated withDepartamento de Farmacologia, Faculdade de Medicina da Universidade de Coimbra
  • , Celeste BentoAffiliated withHospital Pediátrico de Coimbra
  • , Carla MarquesAffiliated withHospital Pediátrico de Coimbra
  • , Assunção AtaídeAffiliated withDirecção Regional de Educação da Região Centro
  • , Teresa S. MiguelAffiliated withDirecção Regional de Educação da Região Centro
    • , Jason H. MooreAffiliated withComputational Genetics Laboratory, Department of Genetics, Dartmouth Medical School
    • , Guiomar OliveiraAffiliated withHospital Pediátrico de Coimbra
    • , Astrid M. VicenteAffiliated withInstituto Gulbenkian de CiênciaInstituto Nacional de Saúde Dr. Ricardo Jorge Email author 

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Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (= 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.