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

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Abstract

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 (P = 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.

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Acknowledgments

We thank the autistic patients, their relatives and the healthy blood donors for their collaboration in this study. This work was supported by a Portuguese grant from the Fundação para a Ciência e a Tecnologia (FCT) (POCTI/39636/ESP/2001). Ana M. Coutinho was supported by a grant from FCT (SFRH/BD/3145/2000) and from the Fundo Social Europeu (III Quadro Comunitário de Apoio).

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Authors and Affiliations

  1. Instituto Gulbenkian de Ciência, R. Quinta Grande 6, Ap. 14, 2781-901, Oeiras, Portugal

    Ana M. Coutinho, Inês Sousa, Madalena Martins, Catarina Correia & Astrid M. Vicente

  2. Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016, Lisbon, Portugal

    Madalena Martins, Catarina Correia & Astrid M. Vicente

  3. Departamento de Farmacologia, Faculdade de Medicina da Universidade de Coimbra, R. Larga, 3004-504, Coimbra, Portugal

    Teresa Morgadinho

  4. Hospital Pediátrico de Coimbra, Av. Bissaya Barreto, 3000-076, Coimbra, Portugal

    Celeste Bento, Carla Marques & Guiomar Oliveira

  5. Direcção Regional de Educação da Região Centro, R. General Humberto Delgado 319, 3030-327, Coimbra, Portugal

    Assunção Ataíde & Teresa S. Miguel

  6. Computational Genetics Laboratory, Department of Genetics, Dartmouth Medical School, Lebanon, NH, 03756, USA

    Jason H. Moore

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  1. Ana M. Coutinho
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  2. Inês Sousa
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Correspondence to Astrid M. Vicente.

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439_2006_301_MOESM1_ESM.doc

Supplementary Table S1 Polymorphisms studied and respective reference or primer sequences used for amplification (DOC 420 kb)

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Coutinho, A.M., Sousa, I., Martins, M. et al. Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Hum Genet 121, 243–256 (2007). https://doi.org/10.1007/s00439-006-0301-3

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