Heritability of the melatonin synthesis variability in autism spectrum disorders

Marion Benabou,Gaël A Millot,Thomas Rolland,Cécile Pagan,Richard Delorme,Erik Maronde,Marion Leboyer,Guillaume Huguet,Jacques Callebert,Claire S Leblond,Thomas Bourgeron

doi:10.1038/s41598-017-18016-3

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.

Highlights

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by deficits in social communication/interaction as well as restricted interests and repetitive patterns of behaviors
Melatonin derives from serotonin, which is successively converted into N-acetylserotonin (NAS) and melatonin by the enzymes arylalkylamine N-acetyltransferase (AANAT, EC: 2.3.1.87) and acetylserotonin O-methyltransferase (ASMT, EC: 2.1.1.4)
These alterations were observed to a lesser extent, in the relatives of patients with ASD, compared to controls[10,15], but familial correlations and heritability have never been assessed for both steps of the melatonin synthesis pathway in families with ASD

Summary

Introduction

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by deficits in social communication/interaction as well as restricted interests and repetitive patterns of behaviors. Observed in patients compared to relatives and controls, including hyperserotonemia, deficits in AANAT and ASMT platelet activity, increased platelet NAS and melatonin deficit[10,15] These alterations were observed to a lesser extent, in the relatives of patients with ASD, compared to controls[10,15], but familial correlations and heritability have never been assessed for both steps of the melatonin synthesis pathway in families with ASD. Melatonin is a pleiotropic neuroendocrine molecule essential for synchronizing circadian and seasonal rhythms, as well as sleep/ wake cycles, and displays antioxidant, neuroprotective, or immunomodulatory effects[20,21,22] Biochemical alterations of this pathway could be related to the core symptoms of autism or the comorbidities such as cognitive problems, epilepsy, sleep and gastrointestinal disorders observed in ASD17,23–25

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