Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n = 250) and compared the allelic frequencies with controls (n = 255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P = 0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P = 2 Â 10
À10). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P = 2 Â 10 À12 ) and melatonin level (P = 3 Â 10 À11 ) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.
These results, based on a statistically validated AAO cut-off and those of previous studies on AAO in OCD, suggest that AAO is a crucial phenotypic characteristic in understanding the genetic basis of this disorder.
Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 1 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. 2 Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele 3 and the other of the long allele. 4 Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. 5,6 These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. 7-9 Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism. Molecular Psychiatry (2002) 7, 67-71. DOI: 10.1038/ sj/mp/4000923Family and twin studies indicate that autism is one of the most strongly genetic neuropsychiatric disorders. 10,11 The pattern of recurrence risk among relatives suggests that several interacting genes are likely to underlie susceptibility to autism. 11 Genetic factors predisposing to autism may also confer a risk for a broader phenotype that extends beyond strictly defined autism to include a range of related but milder behavioral deficits. Indeed, cognitive, social, and language impairments are more frequently observed among relatives of autistic probands than among relatives of controls. 12 Similarly, elevated levels of whole blood or platelet serotonin (5-hydroxytryptamine, 5-HT) have been consistently observed in about one third of autistic subjects 7 and in their first-degree relatives, 8,9,13,14 suggesting that hyperserotonemia may be a marker of genetic susceptibility to autism. Other lines of evidence also suggest that a dysregulation in serotonergic neurotransmission might be involved in the pathogenesis of autism. Short-term dietary depletion of the 5-HT precursor tryptophan results in an exacerbation of behavioral symptoms in autistic subjects. 15 Conversely, 5-HT re-uptake inhibitors, which block the re-uptake of 5-HT into the presynaptic neuron by inhibiting the 5-HT transporter (5-HTT), appear to be of some benefit in the treatment of autistic symptoms such as ritualistic behavior and aggression. 16,17 These data suggest that the 5-HTT is a compelling candidate gene for autism.Two common polymorphisms of the 5-HTT gene have been described, a variable number of tandem repeats...
BackgroundRecent statistical approaches based on factor analysis of obsessive compulsive (OC) symptoms in adult patients have identified dimensions that seem more effective in symptom-based taxonomies and appear to be more stable over time. Although a phenotypic continuum from childhood to adulthood has been hypothesized, no factor analytic studies have been performed in juvenile patients, and the stability of OC dimensions in children and adolescents has not been assessed.MethodsThis study was designed to perform an exploratory factor analysis of OC symptoms in a sample of children and adolescents with OC disorder (OCD) and to investigate the course of factors over time (mean follow-up period: four years).ResultsWe report for the first time that four symptom dimensions, remarkably similar to those previously described in adults, underlined the heterogeneity of OC symptoms in children and adolescents. Moreover, after follow-up, the symptom dimensions identified remained essentially unmodified. The changes observed concerned the intensity of dimensions rather than shifts from one dimension to another.ConclusionThese findings reinforce the hypothesis of a phenotypic continuum of OC symptoms from childhood to adulthood. They also strengthen the interest for investigating the clinical, neurobiological and genetic heterogeneity of OCD using a dimension-based approach.
Several lines of evidence suggest that obsessive compulsive disorder (OCD) could be the consequence of glutamatergic dysfunction. We performed a case-control study in 156 patients and 141 controls and the transmission disequilibrium test in 124 parent-offspring trios to search for association between OCD and two kainate receptors, GRIK2 and GRIK3. Using three single nucleotide polymorphisms (SNP) in GRIK2 and one in GRIK3, we found no evidence for association in case-control or family-based analyses. Only the GRIK2 SNP I867, recently associated with autism, was less transmitted than expected (p < 0.03), supporting a functional role for this variant. These findings suggest the need for further investigation of the role of GRIK2 in OCD.
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