Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism

Instituto Gulbenkian de Ciência, R Quinta Grande, 6, 2781-196 Oeiras, Portugal.
Molecular Psychiatry (Impact Factor: 14.5). 04/2004; 9(3):264-71. DOI: 10.1038/
Source: PubMed


The role of the serotonin system in the etiology and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High levels of platelet serotonin (5-HT) have been consistently found in a proportion of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants modulate transporter reuptake function, therefore possibly influencing the occurrence of hyperserotonemia in a subset of autistic patients. We have examined the association of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control children. Quantitative transmission disequilibrium test (QTDT) results showed a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR; P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with a major contribution of the L.Stin2.10 haplotype (P=0.0013). A 5-HT mean value in the range of hyperserotonemia was associated with the homozygous L.Stin2.10 haplotype (H (1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic patients against 6% of patients with normal 5-HT levels (Fisher's exact test: P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant dominance variance effect on 5-HT levels. We found no transmission disequilibrium of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is a significant factor in the determination of 5-HT levels, and that specific SLC6A4 variants are associated with an increased risk for hyperserotonemia in our sample of autistic patients. The biological mechanism, however, is unlikely to involve the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other genes or environmental factors to produce the abnormally high 5-HT levels observed in this subset of autistic patients, who possibly represent a separate etiological group.

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Available from: Celeste Bento, Apr 30, 2014
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    • "Remarkably, proteins regulating 5-HT homeostasis peripherally and in the central nervous system (CNS) are largely conserved: the SLC6A4 and HTR2A genes encode the same SERT and 5-HT2A receptor, respectively, both in platelets and brain (Cook et al., 1994; Lesch et al., 1993). Several genes involved in SERT trafficking, especially SLC6A4 and ITGB3, were mapped to autism linkage regions, found to host rare variants causing ASD, or were associated with autism through common variants (Cantor et al., 2005; Coutinho et al., 2004; Napolioni et al., 2011; Stone et al., 2004; Weiss et al., 2004. 2006a). "
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    ABSTRACT: Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1–5.2); P=1.0×10−12], and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8–3.9); P=2.7×10−7]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2–2-0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2014; 24(6). DOI:10.1016/j.euroneuro.2014.02.004 · 4.37 Impact Factor
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    • "Interestingly, abnormal levels of these cytokines have been reported in cerebrospinal fluid (Pardo et al., 2005) and brain tissue (Li et al., 2009) from an autism patient with motor skill deficits. Recent studies suggested SLC6A4/HTT might be a candidate gene for autism based on the association of hyperserotonemia with autism (Coutinho et al., 2004). Autism patients have been treated with selective serotonin re-uptake inhibitors which appears to reduce repetitive and aggressive behavior (Posey et al., 2008). "
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    ABSTRACT: Autism spectrum disorders (ASDs) are a group of diseases exhibiting impairment in social drive, communication/language skills and stereotyped behaviors. Though an increased number of candidate genes and molecular interactions have been identified by various approaches, the pathogenesis remains elusive. Based on clinical observations, data from accessible GWAS and expression datasets we identified ASDs gene candidates. Integrative gene network and a novel CNV-centric Node Network (CNN) analysis method highlighted ASDs-associated key elements and biological processes. Functional analysis identified neurological functions including synaptic cholinergic receptor (CHRNA) families, dopamine receptor (DRD2), and correlations between social behavior and oxytocin related pathways. CNN analysis of genome-wide genetic and expression data identified inheritance-related clusters related to PTEN/TSC1/FMR1 and mTor/PI3K regulation. Integrative analysis identified potential regulators of networks, specifically TNF and beta-estradiol, suggesting a potential central role in ASDs. Our data provide information on potential disease mechanisms, and key regulators that may generate novel postulations, and diagnostic molecular biomarkers.
    Gene 04/2012; 496(2):88-96. DOI:10.1016/j.gene.2012.01.020 · 2.14 Impact Factor
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    • "Their findings, provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children (Azmitia et al., 2011) In addition, proinflammatory cytokines IL-1 and TNF are capable of affecting the activity of the serotonin transporter gene, a potential susceptibility gene in ASD (Coutinho et al., 2004). Cytokines and chemokines play a major role in many stages of development of the CNS and are known to induce the secretion of many neurotransmitters and neuropeptides (Biber et al., 2002). "

    Autism - A Neurodevelopmental Journey from Genes to Behaviour, 08/2011; , ISBN: 978-953-307-493-1
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