Dataset Information

Heritability of the melatonin synthesis variability in autism spectrum disorders.

ABSTRACT: Autism Spectrum Disorders (ASD) are heterogeneous neurodevelopmental disorders with a complex genetic architecture. They are characterized by impaired social communication, stereotyped behaviors and restricted interests and are frequently associated with comorbidities such as intellectual disability, epilepsy and severe sleep disorders. Hyperserotonemia and low melatonin levels are among the most replicated endophenotypes reported in ASD, but their genetic causes remain largely unknown. Based on the biochemical profile of 717 individuals including 213 children with ASD, 128 unaffected siblings and 376 parents and other relatives, we estimated the heritability of whole-blood serotonin, platelet N-acetylserotonin (NAS) and plasma melatonin levels, as well as the two enzymes arylalkylamine N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT) activities measured in platelets. Overall, heritability was higher for NAS (0.72?±?0.091) and ASMT (0.59?±?0.097) compared with serotonin (0.31?±?0.078), AANAT (0.34?±?0.077) and melatonin (0.22?±?0.071). Bivariate analyses showed high phenotypic and genetic correlations between traits of the second step of the metabolic pathway (NAS, ASMT and melatonin) indicating the contribution of shared genetic factors. A better knowledge of the heritability of the melatonin synthesis variability constitutes an important step to identify the factors that perturb this pathway in individuals with ASD.

SUBMITTER: Benabou M

PROVIDER: S-EPMC5735101 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Heritability of the melatonin synthesis variability in autism spectrum disorders.

Benabou Marion M Rolland Thomas T Leblond Claire S CS Millot Gaël A GA Huguet Guillaume G Delorme Richard R Leboyer Marion M Pagan Cécile C Callebert Jacques J Maronde Erik E Bourgeron Thomas T

Scientific reports 20171218 1

Autism Spectrum Disorders (ASD) are heterogeneous neurodevelopmental disorders with a complex genetic architecture. They are characterized by impaired social communication, stereotyped behaviors and restricted interests and are frequently associated with comorbidities such as intellectual disability, epilepsy and severe sleep disorders. Hyperserotonemia and low melatonin levels are among the most replicated endophenotypes reported in ASD, but their genetic causes remain largely unknown. Based on ...[more]

PMID: 29255243

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Project description:BackgroundThe etiology of Autism Spectrum Disorder (ASD) has been recently debated due to emerging findings on the importance of shared environmental influences. However, two recent twin studies do not support this and instead re-affirm strong genetic effects on the liability to ASD, a finding consistent with previous reports. This study conducts a systematic review and meta-analysis of all twin studies of ASD published to date and explores the etiology along the continuum of a quantitative measure of ASD.MethodsA PubMed Central, Science Direct, Google Scholar, Web of Knowledge structured search conducted online, to identify all twin studies on ASD published to date. Thirteen primary twin studies were identified, seven were included in the meta-analysis by meeting Systematic Recruitment criterion; correction for selection and ascertainment strategies, and applied prevalences were assessed for these studies. In addition, a quantile DF extremes analysis was carried out on Childhood Autism Spectrum Test scores measured in a population sample of 6,413 twin pairs including affected twins.ResultsThe meta-analysis correlations for monozygotic twins (MZ) were almost perfect at .98 (95% Confidence Interval, .96-.99). The dizygotic (DZ) correlation, however, was .53 (95% CI .44-.60) when ASD prevalence rate was set at 5% (in line with the Broad Phenotype of ASD) and increased to .67 (95% CI .61-.72) when applying a prevalence rate of 1%. The meta-analytic heritability estimates were substantial: 64-91%. Shared environmental effects became significant as the prevalence rate decreased from 5-1%: 07-35%. The DF analyses show that for the most part, there is no departure from linearity in heritability.ConclusionsWe demonstrate that: (a) ASD is due to strong genetic effects; (b) shared environmental effects become significant as a function of lower prevalence rate; (c) previously reported significant shared environmental influences are likely a statistical artefact of overinclusion of concordant DZ twins.

Project description:BackgroundOne consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene.MethodsIn the present study, we have investigated all the genes involved in the melatonin pathway by mutation screening of AA-NAT (arylalkylamine N-acetyltransferase), ASMT, MTNR1A, MTNR1B (melatonin receptor 1A and 1B) and GPR50 (G protein-coupled receptor 50), encoding both synthesis enzymes and the three main receptors of melatonin, in 109 patients with autism spectrum disorders (ASD). A cohort of 188 subjects from the general population was used as a comparison group and was genotyped for the variants identified in the patient sample.ResultsSeveral rare variants were identified in patients with ASD, including the previously reported splice site mutation in ASMT (IVS5+2T>C). Of the variants affecting protein sequence, only the V124I in the MTNR1B gene was absent in our comparison group. However, mutations were found in upstream regulatory regions in three of the genes investigated, ASMT, MTNR1A, and MTNR1B.ConclusionsOur report of another ASD patient carrying the splice site mutation IVS5+2T>C, in ASMT further supports an involvement of this gene in autism. Moreover, our results also suggest that other melatonin related genes might be interesting candidates for further investigation in the search for genes involved in autism spectrum disorders and related neurobehavioral phenotypes. However, further studies of the novel variants identified in this study are warranted to shed light on their potential role in the pathophysiology of these disorders.

Dataset Information

Heritability of the melatonin synthesis variability in autism spectrum disorders.

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Heritability of the melatonin synthesis variability in autism spectrum disorders.

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