Genetic and Functional ascertainment of the Melatonin Pathway in Patients with Attention Deficit and Hyperactivity Disorders
Pauline ChasteNathalie ClémentHany Goubran BotrosJean‐Luc GuillaumeMarina KonyukhCécile PaganIsabelle ScheidGudrun NygrenHenrik AnckarsäterMaria RåstamOla StåhlbergI. Carina GillbergJonas MelkeRichard DelormeClaire S. LeblondRoberto ToroGuillaume HuguetFabien FauchereauChristelle M. DurandLydia BoudarèneEmilie SerranoNathalie LemièreJean Marie LaunayMarion LeboyerRalf JockersChristopher GillbergThomas Bourgeron
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Sleep wake cycles are frequently disturbed in patients with Attention Deficit and Hyperactivity Disorders. We hypothesized that the origin of the sleep problems may be the consequence of an abnormal circadian clock setting regulated by the melatonin pathway. Here, we sequenced all the genes of the melatonin pathway AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 in 328 individuals from Sweden including 108 patients with ADHD and 220 from the general population. Non-synonymous mutations were identified in all genes at a similar frequency in patients with ADHD and in controls. Among the functional variations, a splice site mutation (IVS5+2T>C) in ASMT and one stop mutation (Y170X) in MTNR1A were only detected in patients with ADHD. Biochemical analyses indicated that these mutations abolish the activity of ASMT and MTNR1A. We also identified clusters of SNPs within MTNR1B showing significant difference in the allelic frequency between ADHD patients and control (maximum signal at rs10830961 P=0.0002). Taken together, these genetic and functional results shed light on one new compelling candidate pathway for susceptibility to circadian rhythms alterations that could help clinicians for providing better treatments of patients with ADHD and sleep problems.Cite
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Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.
Splice site mutation
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Abstract: Depressive disorder (DD) is characterised by disturbances in blood melatonin concentration. It is well known that melatonin is involved in the control of circadian rhythms, sleep included. The use of melatonin and its analogues has been found to be effective in depression therapy. Melatonin synthesis is a multistage process, where the last stage is catalysed by acetylserotonin methyltransferase (ASMT), the reported rate‐limiting melatonin synthesis enzyme. Taking into account the significance of genetic factors in depression development, the gene for ASMT may become an interesting focus for studies in patients with recurrent DD. The goal of the study was to evaluate two single‐nucleotide polymorphisms (SNPs) (rs4446909; rs5989681) of the ASMT gene, as well as mRNA expression for ASMT in recurrent DD‐affected patients. We genotyped two polymorphisms in a group of 181 recurrent DD patients and in 149 control subjects. The study was performed using the polymerase chain reaction/restriction fragment length polymorphism method. The distribution of genotypes in both studied SNPs in the ASMT gene differed significantly between DD and healthy subjects. The presence of AA genotype of rs4446909 polymorphism and of GG genotype of rs5989681 polymorphism was associated with lower risk for having recurrent DD. In turn, patients with depression were characterised by reduced mRNA expression for ASMT. In addition, ASMT transcript level in both recurrent DD patients and in healthy subjects depended significantly on genotype distributions in both polymorphisms. In conclusion, our results suggest the ASMT gene as a susceptibility gene for recurrent DD.
Gene polymorphism
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Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents; however, its etiology is unknown. In this study, we investigated the association of five polymorphisms in dopaminergic/GABAergic genes with ADHD using polymerase chain reaction-restriction fragment length polymorphism in a group of 54 children with ADHD and 67 healthy controls. The distribution of AA genotype and A allele frequencies of rs5320 in the dopamine beta-hydroxylase gene in ADHD children differed significantly from that in healthy controls; however, no associations were found between four other polymorphisms in dopaminergic/GABAergic genes and ADHD. We also identified the best model consisting of four loci. We conclude that the rs5320 polymorphism may be considered as a genetic risk factor of ADHD, but the other four polymorphisms were not confirmed to be related directly to ADHD. The multilocus of dopaminergic/GABAergic genes acted in combination to affect susceptibility to ADHD in the children studied.
Dopaminergic pathways
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Melatonin is the most well-known regulator of the circadian rhythms of all living organisms and the main substrate synthesized at night. There are 4 stages in the synthesis of melatonin. This review focuses on the 2nd, 3rd, and 4th stages. The review is aimed at analyzing publications on molecular genetic association studies on the role of single nucleotide polymorphisms (SNPs) of the DDC (AADC), AANAT and ASMT genes encoding melatonin synthesis enzymes in the pathogenesis of socially significant neuropsychiatric disorders in humans. The authors analyzed the available full-text articles from several databases, as well as materials from electronic resources. Search depth was 15 years. The analysis of these studies over the past decade show the association of some SNPs of the studied genes with the risk of neuropsychiatric disorders such as delayed sleep phase disorder, attention deficit hyperactivity disorder, autism spectrum disorder, migraine, Parkinson's disease, depression, anxiety, bipolar-affective disorder, schizophrenia.Мелатонин — наиболее известный регулятор циркадных ритмов и главный субстрат, синтезируемый в темное время суток. В синтезе мелатонина выделяют 4 этапа. Настоящий обзор посвящен второму, третьему и четвертому этапам. Его цель — анализ публикаций, отражающих результаты молекулярно-генетических ассоциативных исследований роли однонуклеотидных полиморфизмов (ОНП) генов DDC (AADC), AANAT и ASMT, кодирующих ферменты синтеза мелатонина, в патогенезе социально значимых психоневрологических расстройств у человека. Проанализированы доступные полнотекстовые статьи в различных базах данных, а также материалы электронных ресурсов. Глубина поиска составила 15 лет. В течение последнего десятилетия показана связь носительства ряда ОНП изучаемых генов с риском развития психоневрологических расстройств, таких как синдром задержки фазы сна, синдром дефицита внимания с гиперактивностью, расстройство аутистического спектра, мигрень, болезнь Паркинсона, тревога, депрессия, биполярное аффективное расстройство, шизофрения.
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Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes (MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study.Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes (MRNR1A, MTNR1B) was then performed for each subject.Four hundred and eighteen inpatients (TD=256, non-TD=162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P=0.037), and the association was also found to be significant by global haplotype analyses (permutation P=0.045).Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated.
Tardive dyskinesia
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The majority of patients with alcohol dependence syndrome suffer from sleep disorders, particularly insomnia, associated with a number of critical clinical aspects, increased suicide risk, anxiety and depression. The authors of relevant publications indicate associations between polymorphic melatonin genes and melatonin metabolism and symptoms of sleep disorders. However, the literature review failed to reveal any studies on the role of genetic polymorphism of circadian rhythm regulators in sleep disorders in patients with alcohol dependence. Objective : to determine the associations of polymorphic variants of genes HTR2A, MTNR1A, MTNR1B, CLOCK, DRD2 with sleep disorders risk in alcohol dependence syndrome. Patients and methods . 307 patients with alcohol dependence syndrome were screened, including 61 women (21%) and 246 (79%) men (mean age – 41.92±7.9 years). The presence and severity of sleep disorders were assessed by the Insomnia Severity Index. In addition, 10 ml of venous blood sample was obtained from all participants. Genotyping of single nucleotide variants of HTR2A (rs6313), MTNR1A (rs34532313), MTNR1B (rs10830963), CLOCK (rs1801260), DRD2 (rs1800497) genes was performed using real-time polymerase chain reaction. Statistical analysis of the data was conducted using parametric and nonparametric methods. Results and discussion . The carriage of the *G allele of the polymorphic variant of the MTNR1B (rs10830963) gene, and its genotypes are associated with a greater risk of insomnia than the carriage of *С/*С genotype. The carriage of the *С allele of the polymorphic variant of the CLOCK (rs1801260) gene, as well as the *С/*Т genotype, are associated with the presence of sleep disorders. No associations between polymorphic variants of the HTR2A (rs6313), DRD2 (rs1800497) genes and insomnia risk were detected in patients with alcohol dependence syndrome. Conclusion . The found associations reveal prospects for future research on melatonin's role in the pathophysiology of sleep disorders in patients with alcohol dependence and pathogenetic therapy for insomnia.
Alcohol Dependence
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Patients affected by bipolar disorder (BD) frequently report abnormalities in sleep/wake cycles. In addition, they showed abnormal oscillating melatonin secretion, a key regulator of circadian rhythms and sleep patterns. The acetylserotonin O-methyltransferase (ASMT) is a key enzyme of the melatonin biosynthesis and has recently been associated with psychiatric disorders such as autism spectrum disorders and depression. In this paper, we analysed rare and common variants of ASMT in patients with BD and unaffected control subjects and performed functional analysis of these variants by assaying the ASMT activity in their B-lymphoblastoid cell lines. We sequenced the coding and the regulatory regions of the gene in a discovery sample of 345 patients with BD and 220 controls. We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10−4) and a lower enzymatic activity (P< 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD.
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Gene polymorphism
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Objective:To investigate the relationship between the three functional polymorphisms in the promoter region of dopamine D4 receptor(DRD4) gene and attention deficit hyperactivity disorder(ADHD).Methods:166 unrelated patients with ADHD and 166 healthy unrelated individuals were genotyped by allele specific amplification(ASA)and polymerase chain reaction(PCR) and then electrophoresis on 2% or 2.5% agarose gels.Results:There were no significant differences in genotype and allele distribution at-1240L/S and-616C/G.The genotype distribution between ADHD patients and controls was different at-521C/T(x2= 9.733,p=0.008),the T allele frequency was significantly higher in ADHD patients compared with that in controls(x2 =9.827,p=0.002,OR=1.639,95%CI=1.202-2.234),which indicated that T allele was a risk factor for susceptibility to ADHD.Conclusions:There is association between the DRD4-521C/T polymorphism and ADHD.The individuals with-521T allele were susceptible to this disorder.
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