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

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.

Genes Controlling Affiliative Behavior as Candidate Genes for Autism

“…Correspondingly, at this point, all that can be said is that these results indicate the presence of statistical association between various aspects of the ASD phenotypes and the genes of interest. These associations need to be investigated further for replication and confirmation purposes (51), their translation into the understanding of the underlying biology (52), an appreciation of possible higher order-effects between multiple genetic variants (53), and the role of formative early environmental events (7) in intensifying or diminishing genetic risk.…”

Aggressive behavior, related conduct problems, and variation in genes affecting dopamine turnover

“…Models effective in group differentiation are likely to generalize to independent datasets and are characterized by high CVC and accuracy, specificity, and sensitivity greater than .5. MDR is a relatively new approach, and the software, although it has been successfully applied [Andrew et al, 2006;Coutinho et al, 2007;Huang et al, 2007;Li et al, 2008;Ni et al, 2009;Park et al, 2007], has not yet penetrated the psychological literature, although there have been analogous attempts to consider multiple configurations of various risk, even if not genetic, factors for theory [Magnusson, 1999], for methodology [Lienert et al, 1990], and for illustration [Eklund et al, 2005]. The issue of multiple comparisons was handled differently for the different types of analyses (see below).…”

Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes

“…10,11 Interestingly, ITGB3 maps under a replicated linkage peak for autism. 12,13 Furthermore, ITGB3 alleles have been found at least nominally associated with autism in all five studies performed to date, [14][15][16][17][18] either alone or in interaction with allelic variants at the 5-HT transporter gene (SLC6A4). Several lines of evidence support functional interactions between ITGB3 and SLC6A4, which also affects 5-HT blood levels and is located on human chromosome 17q11.1-q12.…”