Noradrenergic genes polymorphisms and response to methylphenidate in children with ADHD

Yuan, Danfeng; Zhang, Manxue; Huang, Yan; Wang, Xinwei; Jiao, Jian; Huang, Yi

doi:10.1097/md.0000000000027858

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…This can explain the role of norepinephrine reuptake inhibitors in patients with ADHD. Noradrenergic gene polymorphisms can affect the efficacy of methylphenidate and atomoxetine in children with ADHD according to the meta-analysis ( Gul et al, 2021 ; Yuan et al, 2021 ). The reported genes include DBH , DRD4, NET1 / SLC6A2 , ADRA2A , and ADRA2C .…”

Section: Resultsmentioning

confidence: 99%

Attention-deficit/hyperactive disorder updates

Kessi

Duan

Xiong

et al. 2022

Front. Mol. Neurosci.

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BackgroundAttention-deficit/hyperactive disorder (ADHD) is a neurodevelopmental disorder that commonly occurs in children with a prevalence ranging from 3.4 to 7.2%. It profoundly affects academic achievement, well-being, and social interactions. As a result, this disorder is of high cost to both individuals and society. Despite the availability of knowledge regarding the mechanisms of ADHD, the pathogenesis is not clear, hence, the existence of many challenges especially in making correct early diagnosis and provision of accurate management.ObjectivesWe aimed to review the pathogenic pathways of ADHD in children. The major focus was to provide an update on the reported etiologies in humans, animal models, modulators, therapies, mechanisms, epigenetic changes, and the interaction between genetic and environmental factors.MethodsReferences for this review were identified through a systematic search in PubMed by using special keywords for all years until January 2022.ResultsSeveral genes have been reported to associate with ADHD: DRD1, DRD2, DRD4, DAT1, TPH2, HTR1A, HTR1B, SLC6A4, HTR2A, DBH, NET1, ADRA2A, ADRA2C, CHRNA4, CHRNA7, GAD1, GRM1, GRM5, GRM7, GRM8, TARBP1, ADGRL3, FGF1, MAOA, BDNF, SNAP25, STX1A, ATXN7, and SORCS2. Some of these genes have evidence both from human beings and animal models, while others have evidence in either humans or animal models only. Notably, most of these animal models are knockout and do not generate the genetic alteration of the patients. Besides, some of the gene polymorphisms reported differ according to the ethnic groups. The majority of the available animal models are related to the dopaminergic pathway. Epigenetic changes including SUMOylation, methylation, and acetylation have been reported in genes related to the dopaminergic pathway.ConclusionThe dopaminergic pathway remains to be crucial in the pathogenesis of ADHD. It can be affected by environmental factors and other pathways. Nevertheless, it is still unclear how environmental factors relate to all neurotransmitter pathways; thus, more studies are needed. Although several genes have been related to ADHD, there are few animal model studies on the majority of the genes, and they do not generate the genetic alteration of the patients. More animal models and epigenetic studies are required.

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Section: Resultsmentioning

confidence: 99%

Attention-deficit/hyperactive disorder updates

Kessi

Duan

Xiong

et al. 2022

Front. Mol. Neurosci.

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“…These genes were enriched for BPs involved in cell morphogenesis and adhesion, but also synaptic transmission and signalling with a focus on catecholamines and GABAergic transmission. Considering that this is an in vitro system, the findings are compelling since structural cortical changes and catecholaminergic transmission have been the target of various epidemiological studies and drug clinical trials, both in children and adults with ADHD (67–70).…”

Section: Discussionmentioning

confidence: 99%

“…The genes were enriched for BPs involved in cell morphogenesis and adhesion, but also synaptic transmission and signalling with a focus on catecholamines and GABAergic transmission. Considering that this is an in vitro system, the findings are compelling since structural cortical changes and catecholaminergic transmission have been the target of various epidemiological studies and drug clinical trials, both in children and adults with ADHD [77][78][79][80] . It is biologically plausible that medications that cross the placenta and the blood-brain barrier, may interfere with normal fetal brain neurodevelopment, previously shown for valproic acid, and more recently for topiramate 81 .…”

Section: Discussionmentioning

confidence: 99%

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Spildrejorde

Samara

Sharma

et al. 2022

Preprint

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Background: Several epidemiological studies have found associations between long-term prenatal exposure to paracetamol and neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies have identified differences in DNA methylation (DNAm) in cord blood between exposed and unexposed neonates. However, the causal implications and impact of prenatal long-term paracetamol exposure on brain development are not known. Methods: We exposed human embryonic stem cells (hESCs) undergoing in vitro neuronal differentiation to daily changes of media containing amount of paracetamol corresponding to human foetal exposure with maternal therapeutic doses. An integrated multi-omics approach was used to investigate epigenetic and transcriptomic effects of paracetamol on the early stages of human brain development. Results: Multi-omics analyses of DNAm, chromatin opening, and gene expression identified dose-dependent effects on cell proliferation and maturation. We found differentially methylated and/or expressed genes involved in signal transduction, neurotransmitter secretion and cell fate determination trajectories. Integration of single-cell RNA-seq and ATAC-seq showed that paracetamol-induced changes in chromatin opening were linked to transcription. For example, EP300 encoding a histone acetyltransferase and H3K27ac were linked to many putative cis regulatory elements and downregulated upon paracetamol exposure. Some of the genes are involved in neuronal injury, response to toxic insults and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Conclusion: We identified dose-dependent epigenetic and transcriptional changes in hESCs undergoing neuronal differentiation after paracetamol exposure. The overlap of differentially methylated genes with our previous analysis in cord blood from children exposed to paracetamol during pregnancy could suggest a causal role in impaired neurodevelopment.

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“…Some stimulants, such as amphetamines, and non-stimulants, such as atomoxetine, have been reported to be substrates of cytochrome P450s, and their performance has been linked to CYP2D6 genotype [ 41 , 42 ]. While MPH’s US Food and Drug Administration (FDA) label does not contain pharmacogenomic biomarkers, a lot of research has been performed on the impact of genotype on MPH efficacy, and several biological pathways have been suggested to potentially affect MPH mechanisms through patient genotype, mostly concerning monoamine pathways [ 43 – 48 ]. Although the research in this field has been increasing in recent years, and has the potential to affect prescription and possibly improve the outcomes of patients with ADHD [ 49 ], no clear guidelines have been developed and there is still much to understand in this regard [ 50 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review

2022

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Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by persistent inattention, hyperactivity and impulsivity. Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.). The ADHD symptomatology interferes with subject function and development. The treatment of ADHD requires a multidisciplinary approach based on a combination of non-pharmacological and pharmacological treatments with the aim of ameliorating the symptomatology; among first-line pharmacological treatments are stimulants [such as methylphenidate (MPH) and lisdexamfetamine dimesylate (LDX)]. In this review we explored recent ADHD- and stimulants-related literature, with the aim of compiling available descriptions of molecular pathways altered in ADHD, and molecular mechanisms of current first-line stimulants MPH and LDX. While conducting the narrative review, we applied structured search strategies covering PubMed/MEDLINE database and performed handsearching of reference lists on the results of those searches. The aetiology and pathophysiology of ADHD are incompletely understood; both genetic and environmental factors have been associated with the disorder and its grade of burden, and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications. The lack of comprehensive understanding of the underlying molecular pathology makes both the diagnosis and treatment difficult. Few published studies evaluating molecular data on the mechanism of action (MoA) of MPH and LDX on ADHD are available and most of them are based on animal models. Further studies are necessary to improve the knowledge of ADHD pathophysiology and how the MoAs of MPH and LDX differentially modulate ADHD pathophysiology and control ADHD symptomatology.

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Noradrenergic genes polymorphisms and response to methylphenidate in children with ADHD

Abstract: Supplemental Digital Content is available in the text

Cited by 9 publications

References 51 publications

Attention-deficit/hyperactive disorder updates

Attention-deficit/hyperactive disorder updates

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review

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