A polymorphism in the promoter region of the gene (SLC6A4) encoding this protein, was recently reported to affect protein expression and to be associated with measures of anxiety and depression and with autism (using a family-controlled transmission disequilibrium test (TDT) design).
The authors explored whether variants of two functional polymorphisms of SLC6A4 (5-HTTLPR, intron 2 variable number tandem repeat [2 VNTR]) were related to behavioral characteristics measured by the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule.
However, the interesting finding of strong linkage disequilibrium (LD) between the markers and significant disease-specific distortion in the distribution of HTT-3'UTR-SNP genotypes (T1chi(2)=5.19, P=0.02; OR=2.89, 95% CI=1.13-7.41) and the specific haplotypes of the two markers (LRS=11.85, p(c)=0.02), with higher frequencies of T/T genotype and 10-T haplotype in autistic cases suggests that either these markers or nearby markers of SLC6A4 that are in LD, may pose a risk towards autism in the Eastern Indian population.
These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.
Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB).
The serotonin transporter promoter length polymorphism (5-hydroxytryptamine transporter length polymorphism; 5-HTTLPR) has long been implicated in autism and other psychiatric disorders.
Hyperserotonemia in autism appears to be due to enhanced 5-HT uptake, as free 5-HT levels are normal and the current report of an excess of the long/long 5-HTTLPR genotype in autism could provide a partial molecular explanation for high platelet serotonin content in autism.
Platelet 5-HT uptake rates and affinities (V(max) and K(m)), uptake site densities (B(max)) and 5-HT levels were examined in 31 French individuals with autism genotyped with respect to the 5-HTTLPR.
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 this study, an analysis using the transmission/disequilibrium test (TDT) between the 5-HTT gene promoter polymorphism and autism in 104 trios, all ethnically Japanese, showed no significant linkage disequilibrium (P=0.17).
From this body of work we highlight results from three candidate genes, REELIN (RELN), SEROTONIN TRANSPORTER (5HTT), and ENGRAILED 2 (EN2) and discuss the relevant neuroscience, molecular genetics, and statistical results that suggest involvement of these genes in autism susceptibility.
Overall, we were not able to replicate the findings of the first study on 5-HTT and autism and instead observed a tendency for association of the opposite genetic variant of the gene with the disorder.
This could lead to inconsistent genetic association results, such as those of prior studies on serotonin transporter (5-HTT) gene promoter variants and autistic disorder.
The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism.