Etiology Of Attention Deficit Hyperactivity Disorder Research Articles

How does traditional chinese medicine treat attention deficit hyperactivity disorder-A different understanding and treatment strategy

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, and the incidence in children is increasing year by year. The modern medical field lacks long-acting drugs for the treatment of ADHD and there is an urgent need to investigate new therapeutic drugs or complementary and alternative therapies. Recent studies have found that Traditional Chinese Medicine (TCM) has the advantages of individualization, precise efficacy and minimal side effects in improving attention deficit hyperactivity disorder. This paper reviews the progress of Chinese medicine in the treatment of ADHD in terms of its understanding of the etiology and pathogenesis of ADHD, treatment according to pattern identification and Chinese medicinal preparations.

Seeking connection, autonomy, and emotional feedback: A self-determination theory of self-regulation in attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is one of the most prevalent and highly debated diagnosis for mental disorder in practice today. Two decades of research have substantially contributed to evolving conceptualizations and understanding of the condition. However, this evolution has not been extended to theoretical research. Current cognitive behavioral-based theories aim to identify the etiology of ADHD and experience challenges in accommodating the full spectrum of both neurobiological and behavioral research evidence. Characterizations historically associated with mental illness have generated public stigma, influencing low self-esteem, negative self-concept, and identity development in ADHD individuals. Neurodiversity research and activism recognize a diversity of nonnormative development and highlight the need for alternatives to deficit models of functioning. Recent research in psychology recommends developing approaches beyond symptom control and seeking to develop positive psychological factors and well-being. We propose that the perspective presented by self-determination theory (SDT) on human motivation, self-regulation, and self-determination offers a new understanding of ADHD research evidence and symptomology. According to this theory, humans have a natural tendency toward growth and self-actualization. We propose a framework grounded in SDT that provides an alternative understanding of ADHD neural processing, motivation and engagement, self-regulation, and a potential foundation for treatment approaches with self-determination and positive identity outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Pre-conception folic acid intake and attention deficit and hyperactivity disorder in children

Objectives: Attention Deficit Hyperactivity Disorder (ADHD) is a common disorder in children. It is thought to occur due to the interaction of many genetic and environmental factors during early development. Many studies have been conducted to investigate the etiology of ADHD. Some have investigated neurobiology, and others have investigated malnutrition and trace element deficiency. To investigate the effect of folic acid intake during the pre-conception period in terms of ADHD development. Methods: Five hundred and ninety-eight participants, 246 children with ADHD, and 352 healthy controls were enrolled. A questionnaire was completed, including socio-demographic information and the use of folic acid and other supplements such as a multivitamin, iron, and omega 3 during pregnancy. Data were examined to determine associations with ADHD. Mann-Whitney U tests for continuous variables, Pearson’s chi-square, and Fisher’s exact tests for categorical variables were used to compare groups. Results: The use of folic acid during pre-pregnancy among mothers who had a child with ADHD was 13% and this was 31% in the control group (p < 0.001). There was no statistically significant difference between the groups’ use of folic acid in pregnancy (p = 0.617). Other situations related to ADHD were advanced maternal age (p < 0.001 for both groups), abnormal double screening test results in pregnancy (27% vs. 5%, p < 0.001) and omega 3 use in pregnancy (p < 0.001). Conclusions: The use of folic acid before and during pregnancy is important for neurological development. However, there is little data on use before pregnancy in the literature. This study shows that folic acid taken before pregnancy may prevent ADHD in childhood. The present study recommends folic acid usage in planned pregnancy to prevent ADHD in the child.

Growth rates of human induced pluripotent stem cells and neural stem cells from attention-deficit hyperactivity disorder patients: a preliminary study

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental polygenic disorder that affects more than 5% of children and adolescents around the world. Genetic and environmental factors play important roles in ADHD etiology, which leads to a wide range of clinical outcomes and biological phenotypes across the population. Brain maturation delays of a 4-year lag are commonly found in patients, when compared to controls of the same age. Possible differences in cellular growth rates might reflect the clinical observations in ADHD patients. However, the cellular mechanisms are still not elucidated. To test this hypothesis, we analysed the proliferation of induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) derived from male children and adolescents diagnosed with ADHD and with genetic predisposition to it (assessed using polygenic risk scores), as well as their respective matched controls. In the current pilot study, it was noticeable that NSCs from the ADHD group proliferate less than controls, while no differences were seen at the iPSC developmental stage. Our results from two distinct proliferation methods indicate that the functional and structural delays found in patients might be associated with these in vitro phenotypic differences, but start at a distinct neurodevelopmental stage. These findings are the first ones in the field of disease modelling of ADHD and might be crucial to better understand the pathophysiology of this disorder.

Sex-specific responses to juvenile stress on the dopaminergic system in an animal model of attention-deficit hyperactivity disorder

The etiology of attention-deficit hyperactivity disorder (ADHD) strongly suggests a genetic component as the main cause; however, environmental factors such as early adverse experiences in childhood may play an interactive role with the genetic susceptibility. Spontaneously hypertensive rats (SHRs), a genetic ADHD model, and control Wistar Kyoto rats (WKYs) were subjected to chronic unpredictable mild stress during the juvenile period. The behavioral characteristics were monitored, and dopamine-related factors in the core regions of dopaminergic pathways were measured. Higher ADHD symptom-related behaviors were observed in response to juvenile stress in male SHRs than control WKYs. For the SHRs subjected to juvenile stress, hyperactivity in males, recognition in females, and depressant potential in both sexes were markedly observed. In the expression of 17 dopamine-related genes and proteins, greater changes were detected in male SHRs subjected to juvenile stress, especially in dopamine metabolic factors. Dopamine clearance factors involved in dopamine degradation and transport, especially catechol-O-methyltransferase (COMT) and dopamine transporter (DAT), showed sex-specific differences induced by juvenile stress in dopamine metabolite assays. Moreover, stressed male SHRs treated with methylphenidate showed better improvement in behavior than the females, resulting in different levels of COMT and DAT amelioration. These results suggest that juvenile stress potentially increased the incidence of ADHD in a genetic rat model, which showed sex-specific differences based on the expression of COMT and DAT. Therefore, our results could help develop gender-specific diagnostics and healthcare options for juvenile stress in patients with ADHD.

The distinct role of orbitofrontal and medial prefrontal cortex in encoding impulsive choices in an animal model of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder affecting up to 5% of children worldwide. The lack of understanding of ADHD etiology prevented the development of effective treatment for the disease. Here, using in vivo electrophysiology recordings, we have recorded and analyzed the neuronal encoding of delay discounting behavior in prefrontal and orbitofrontal cortex of spontaneously hypertensive rat (SHR). We found that in the presence of rewards, neurons in the orbitofrontal cortex (OFC) were activated regardless to the value of the rewards and OFC neurons in SHR exhibited significantly higher rates of neuronal discharging towards the presence of rewards. While in the medial prefrontal cortex (mPFC), neurons of SHR responded similarly in the presence of large rewards compared with control rats whereas they displayed higher firing rates towards smaller rewards. In addition, the reward-predicting neurons in the OFC encodes for value of rewards in control animals and they were strongly activated upon receiving a small immediate reinforcer in the SHR whereas the reward-predicting neurons in the mPFC neurons generally did not respond to the value of the rewards. Our study characterized the neuronal discharging patterns of OFC and mPFC neurons in the SHR and the control animals and provided novel insights for further understanding the neuronal basis of ADHD pathology.

Relationship between suicidal behavior/self-mutilation and Vitamin B12 and Folic Acid Levels in Adult Attention Deficit Hyperactivity Disorder

Aim: Attention deficit hyperactivity disorder (ADHD) and suicidal behavior are common situations that cause social and emotional problems. deficiencies of folate and vitamin B12 have been related to suicidal behavior and etiology of ADHD. We aimed to evaluate the association of suicide/self-mutilation behaviors and Vitamin B12 and folic acid levels in adult ADHD. Materials and Methods: Adult ADHD patients were evaluated in terms of sociodemographic characteristics and suicidal behavior/self-mutilation, suicide ideation, impulsivity, functionality with clinical interviews and scales. Comorbid psychiatric diagnosis were excluded. Levels of vitamin B12 and folate were detected. All results were compared to healthy controls statistically. Then ADHD patients were divided into two groups as with and without suicidal behavior/self-mutilation and compared clinically. Results: There were 40 ADHD patients and 40 healthy controls in the study. Suicidal behavior/self-mutilation, suicide ideation and impulsivity scores and psychiatric diagnose history of first degree relatives were higher in the patient group. Levels of Vitamin B12 and folic acid were similar in both groups and not correlated with suicidal behavior/self-mutilation and suicidal ideation. Conclusion: There was a significant association of adult ADHD and suicidal behavior/self-mutilation. Suicide-related consequences were particularly related to impulsivity. It may be recommended to screen individuals with ADHD for suicidal ideation and impulsivity to reduce risky behaviors. However, it does not support the hypothesis of a relationship between low B12 and folate and suicidality in adult ADHD.

TTLL11 gene is associated with sustained attention performance and brain networks: A genome-wide association study of a healthy Chinese sample.

Genetic studies on attention have mainly focused on children with attention-deficit/hyperactivity disorder (ADHD), so little systematic research has been conducted on genetic correlates of attention performance and their potential brain mechanisms among healthy individuals. The current study included a genome-wide association study (GWAS, N=1145 healthy young adults) aimed to identify genes associated with sustained attention and an imaging genetics study (an independent sample of 483 healthy young adults) to examine any identified genes' influences on brain function. The GWAS found that TTLL11 showed genome-wide significant associations with sustained attention, with rs13298112 as the most significant SNP and the GG homozygotes showing more impulsive but also more focused responses than the A allele carriers. A retrospective examination of previously published ADHD GWAS results confirmed an un-reported, small but statistically significant effect of TTLL11 on ADHD. The imaging genetics study replicated this association and showed that the TTLL11 gene was associated with resting state activity and connectivity of the somatomoter network, and can be predicted by dorsal attention network connectivity. Specifically, the GG homozygotes showed lower brain activity, weaker brain network connectivity, and non-significant brain-attention association compared to the A allele carriers. Expression database showed that expression of this gene is enriched in the brain and that the G allele is associated with lower expression level than the A allele. These results suggest that TTLL11 may play a major role in healthy individuals' attention performance and may also contribute to the etiology of ADHD.

Kainate receptor subunit 1 (GRIK1) risk variants and GRIK1 deficiency were detected in the Indian ADHD probands

Executive dysfunctions caused by structural and functional abnormalities of the prefrontal cortex were reported in patients with Attention deficit hyperactivity disorder (ADHD). Owing to a higher expression of the glutamate ionotropic receptor kainate type subunit 1 (GluK1), encoded by the GRIK1 gene, in brain regions responsible for learning and memory, we hypothesized that GRIK1 might have a role in ADHD. GRIK1 variants rs363504 and rs363538, affecting the receptor function, were analyzed by case–control and family-based methods to identify the association with ADHD. The impact of these variants on ADHD-associated traits and pharmacological intervention were also analyzed. GRIK1 expression was quantified in the peripheral blood. The probands and their fathers had a higher frequency of rs363504 ‘CC’ and rs363538 ‘CA’ genotypes. Family-based investigation revealed maternal over transmission of rs363504 ‘C’ and rs363538 ‘A’ alleles to the probands. Quantitative trait analysis exhibited an association of rs363504 ‘TT’ and rs363538 ‘AA’ genotypes with higher hyperactivity scores of the probands. In the presence of rs363504 ‘TT’ and rs363538 ‘CC’ genotypes, MPH treatment improved hyperactivity and inattention, respectively. GRIK1 expression was significantly downregulated in the probands. We infer that GRIK1 affects ADHD etiology, warranting further in-depth investigation involving a larger cohort and more functional variants.

Attention deficit in children with attention deficit hyperactivity disorder at primary school age measured with the attention network test (ANT): A protocol for a systematic review and meta-analysis.

Attentional deficits are among the most bothersome symptoms of attention deficit hyperactivity disorder (ADHD). To date, the neurological basis of attentional deficits has not been fully described according to the diagnostic criteria. ADHD may result from deficits in various attributes of attention. There is no specialist neuropsychological diagnostic method that allows reliable distinction between primary attention disorders in the etiology of ADHD and secondary problems that may arise due to co-morbidities. This protocol aims to systematically review the literature to evaluate patterns of attention common to school-age children either diagnosed with ADHD or at high risk of ADHD, as measured by the neuropsychological attention network test (ANT). Our search strategy will consist of electronic databases (PubMed, PsychInfo, Web of Science, EMBASE, and Cochrane Library) and hand searching. Both prospective cohort studies and prospective studies of intervention effects will be included, provided they used the ANT. The primary output variable will be attention deficits. Screening and eligibility will be done independently by two reviewers based on pre-specified eligibility criteria. Data extraction will be based on a pre-pilot data extraction form and conducted by two authors independently. The risk of bias will be assessed by two authors independently. The rating of the certainty of the entire body of evidence will be evaluated using the GRADE approach. Any discrepancies identified at any stage of the review will be resolved by discussion or/and consultation with another reviewer. We plan a narrative synthesis of findings and a quantitative meta-analysis if the data allow. The research will identify patterns of neuropsychological ANT results characteristic of both school-age children diagnosed with ADHD and those at high risk of having ADHD. Our results could be used to check whether the pattern of a child's performance in the ANT corresponds to the characteristic pattern of the results of children with ADHD. At present, the ANT is used only in research; the results of this review will serve as a useful benchmark. Hopefully, in the future, it will be possible to use the ANT in the wider diagnosis of ADHD. PROSPERO: CRD42021249768.

Common genetic risk factors in ASD and ADHD co-occurring families.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two major neurodevelopmental disorders that frequently co-occur. However, the genetic mechanism of the co-occurrence remains unclear. The New Jersey Language and Autism Genetics Study (NJLAGS) collected more than 100 families with at least one member affected by ASD. NJLAGS families show a high prevalence of ADHD and provide a good opportunity to study shared genetic risk factors for ASD and ADHD. The linkage study of the NJLAGS families revealed regions on chromosomes 12 and 17 that are significantly associated with ADHD. Using whole-genome sequencing data on 272 samples from 73 NJLAGS families, we identified potential risk genes for ASD and ADHD. Within the linkage regions, we identified 36 genes that are associated with ADHD using a pedigree-based gene prioritization approach. KDM6B (Lysine Demethylase 6B) is the highest-ranking gene, which is a known risk gene for neurodevelopmental disorders, including ASD and ADHD. At the whole-genome level, we identified 207 candidate genes from the analysis of both small variants and structure variants, including both known and novel genes. Using enrichment and protein-protein interaction network analyses, we identified gene ontology terms and pathways enriched for ASD and ADHD candidate genes, such as cilia function and cation channel activity. Candidate genes and pathways identified in our study improve the understanding of the genetic etiology of ASD and ADHD and will lead to new diagnostic or therapeutic interventions for ASD and ADHD in the future.

Genetic identification of tissues and cell types underlying attention-deficit/hyperactivity disorder.

BackgroundGenome-wide association studies (GWASs) have identified numerous genetic variants associated with attention-deficit/hyperactivity disorder (ADHD), which is considered highly genetically heritable. However, because most of the variants located in the non-coding region of the human genome, the onset of ADHD requires further exploration.MethodsThe risk genes involved in ADHD were identified by integrating GWAS summary data and expression quantitative trait locus (eQTL) data using summary-data-based Mendelian randomization (SMR) method. We then used a stratified linkage disequilibrium score regression (LDSR) method to estimate the contribution of ADHD-relevant tissues to its heritability to screen out disease-relevant tissues. To determine the ADHD-relevant cell types, we used an R package for expression-weighted cell type enrichment (EWCE) analysis.ResultsBy integrating the brain eQTL data and ADHD GWAS data using SMR, we identified 247 genes associated with ADHD. The LDSR applied to specifically expressed genes results showed that the ADHD risk genes were mainly enriched in brain tissue, especially in the mesencephalon, visual cortex, and frontal lobe regions. Further cell-type-specific analysis suggested that ADHD risk genes were highly expressed in excitatory neurons.ConclusionThe study showed that the etiology of ADHD is associated with excitatory neurons in the midbrain, visual cortex, and frontal lobe regions.

Attention-Deficit/Hyperactivity Disorder and the Gut Microbiota–Gut–Brain Axis: Closing Research Gaps through Female Inclusion in Study Design

The gastrointestinal tract harbors a densely populated community of microbes that exhibits sexual dimorphism. Dysbiosis of this community has been associated with chronic human disease states ranging from metabolic diseases to neuropsychiatric disorders (NPDs). The gut microbiota–gut–brain axis (GMGBA) is a bi-directional pathway that facilitates the interaction of the gut microflora with host physiological functions. Recently, research surrounding the potential roles of the GMGBA in the development of NPDs (e.g., depression, anxiety, and autism spectrum disorders (ASDs)) has increased. However, the role of the GMGBA in attention-deficit/hyperactivity disorder (ADHD), an NPD that affects an estimated 8.4% of children (5.1% of female and 11.5% of male children) and 4% of adults (with a male–female odds ratio of 1.6) in the United States, remains understudied. Herein, we synthesize the current literature regarding the GMGBA, ADHD, and the potentially relevant intersections between the GMGBA and ADHD. Recommendations are presented for pathways of future research into the role(s) of the GMGBA in ADHD etiology and symptomatology. Particular focus is given to the potential for the variable of host sex to act as an outcome modifier of the relationship between the GMGBA and ADHD.

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

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.

Targeting PI3K by Natural Products: A Potential Therapeutic Strategy for Attention-deficit Hyperactivity Disorder.

Attention-Deficit Hyperactivity Disorder (ADHD) is a highly prevalent childhood psychiatric disorder. In general, a child with ADHD has significant attention problems with difficulty concentrating on a subject and is generally associated with impulsivity and excessive activity. The etiology of ADHD in most patients is unknown, although it is considered to be a multifactorial disease caused by a combination of genetics and environmental factors. Diverse factors, such as the existence of mental, nutritional, or general health problems during childhood, as well as smoking and alcohol drinking during pregnancy, are related to an increased risk of ADHD. Behavioral and psychological characteristics of ADHD include anxiety, mood disorders, behavioral disorders, language disorders, and learning disabilities. These symptoms affect individuals, families, and communities, negatively altering educational and social results, strained parent-child relationships, and increased use of health services. ADHD may be associated with deficits in inhibitory frontostriatal noradrenergic neurons on lower striatal structures that are predominantly driven by dopaminergic neurons. Phosphoinositide 3-kinases (PI3Ks) are a conserved family of lipid kinases that control a number of cellular processes, including cell proliferation, differentiation, migration, insulin metabolism, and apoptosis. Since PI3K plays an important role in controlling the noradrenergic neuron, it opens up new insights into research on ADHD and other developmental brain diseases. This review presents evidence for the potential usefulness of PI3K and its modulators as a potential treatment for ADHD.

Altered Arginine/Nitric Oxide Pathway in Children Diagnosed Attention Deficit Hyperactivity Disorder, and the Effect of 10 Weeks Methylphenidate Treatment.

ObjectiveIn this study, we investigated the levels of arginine, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and adrenomedullin that are presumed to play a role in attention deficit hyperactivity disorder (ADHD) etiology, and to compare the findings with healthy controls.MethodsThirty ADHD patients and thirty healthy control subjects aged 6−12 years were included in the study. Sociodemographic data form, Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version; Conners’ Parent/Teacher Rating Scale-Revised Long Form; Children’s Depression Inventory; and The State-Trait Anxiety Inventory for Children were applied to all cases. All participants included in the study were evaluated in terms of their serum arginine, NO, ADMA, and adrenomedullin levels. Subsequently, methylphenidate treatment was started in ADHD patients and blood parameters were tested again in the tenth week of treatment.ResultsAt the start of the study, arginine and ADMA levels were significantly higher and NO and adrenomedullin levels were significantly lower in the ADHD group compared to the control group. Post-treatment arginine and ADMA levels were found to be significantly lower than in the pre-treatment period. There were no significant differences in NO and adrenomedullin levels before and after treatment. There was no correlation between scale scores and blood parameters.ConclusionThese variations in the blood parameters of the ADHD group seem to be worth further investigation. Studies to be conducted with larger sample groups after longer-term treatment may provide new information about the alterations in neurobiological processes related to ADHD etiology and treatment.

Fruit and vegetable intake is inversely associated with severity of inattention in a pediatric population with ADHD symptoms: the MADDY Study

ABSTRACT Objectives: Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder with a U.S. pediatric prevalence of 8–10%. It presents with inattention and hyperactivity/impulsivity; frequently associated with emotional dysregulation (ED) symptoms common in Oppositional Defiant Disorder and Disruptive Mood Dysregulation Disorder. The etiology of ADHD is multi-factorial; symptom severity is associated with diet. This study examines the association of diet quality with ADHD and ED symptoms within a pediatric research cohort. Methods: Baseline data were analyzed for 134 children aged 6–12 years with symptoms of ADHD and ED enrolled in an RCT of multinutrient supplementation. Diet quality was based on Healthy Eating Index-2015 (HEI-2015). ADHD and ED symptoms were assessed using Child and Adolescent Symptom Inventory-5 and Strengths and Difficulties Questionnaire. Linear regression models, adjusting for covariates when necessary, determined association. Results: The mean HEI Total Score of 63.4 (SD = 8.8) was not significantly associated with any outcome symptoms. However, after adjusting for covariates, HEI component scores for total fruit intake (β = −0.158, p = .037) and total vegetable intake (β = −0.118, p = .004) were negatively associated with inattention. Conclusions: The lack of association with total diet quality could be explained by the relatively good baseline diet quality and mild symptom severity in this sample, along with measurement error from dietary intake estimates and relatively small sample size. These findings suggest that dietary intake may impact inattention in children with ADHD and ED: those eating less fruits and vegetables were likely to have more severe symptoms of inattention. Causality is not established by this cross-sectional analysis.

Convergent selective signaling impairment exposes the pathogenicity of latrophilin-3 missense variants linked to inheritable ADHD susceptibility

Latrophilin-3 (Lphn3; also known as ADGRL3) is a member of the adhesion G Protein Coupled Receptor subfamily, which participates in the stabilization and maintenance of neuronal networks by mediating intercellular adhesion through heterophilic interactions with transmembrane ligands. Polymorphisms modifying the Lphn3 gene are associated with attention-deficit/hyperactivity disorder (ADHD) in children and its persistence into adulthood. How these genetic alterations affect receptor function remains unknown. Here, we conducted the functional validation of distinct ADHD-related Lphn3 variants bearing mutations in the receptor’s adhesion motif-containing extracellular region. We found that all variants tested disrupted the ability of Lphn3 to stabilize intercellular adhesion in a manner that was distinct between ligands classes, but which did not depend on ligand-receptor interaction parameters, thus pointing to altered intrinsic receptor signaling properties. Using G protein signaling biosensors, we determined that Lphn3 couples to Gαi1, Gαi2, Gαs, Gαq, and Gα13. However, all ADHD-related receptor variants consistently lacked intrinsic as well as ligand-dependent Gα13 coupling efficiency while maintaining unaltered coupling to Gαi, Gαs, and Gαq. Consistent with these alterations, actin remodeling functions as well as actin-relevant RhoA signaling normally displayed by the constitutively active Lphn3 receptor were impeded by select receptor variants, thus supporting additional signaling defects. Taken together, our data point to Gα13 selective signaling impairments as representing a disease-relevant pathogenicity pathway that can be inherited through Lphn3 gene polymorphisms. This study highlights the intricate interplay between Lphn3 GPCR functions and the actin cytoskeleton in modulating neurodevelopmental cues related to ADHD etiology.

MEF2C gene variations are associated with ADHD in the Chinese Han population: a case-control study.

Myocyte enhancer factor 2C (MEF2C) is associated with hyperactivity and might be a novel risk gene for susceptibility to attention deficit hyperactivity disorder (ADHD). Therefore, this study aimed to explore the association between MEF2C genetic variants and ADHD in the Chinese Han population. A total of 215 patients with ADHD and 233 controls were recruited for this study. The Swanson, Nolan, and Pelham version IV questionnaire was used to evaluate the clinical features of ADHD. In silico analysis was used to annotate the biological functions of the promising single nucleotide polymorphisms. Our findings indicated that MEF2C rs587490 was significantly associated with ADHD in the multiplicative model (OR = 0.640, p = 0.002). Participants with the rs587490 TT allele exhibited less hyperactivity/impulsivity than those with the rs587490 CC allele. Furthermore, the expression quantitative trait loci analysis suggested that rs587490 could regulate the gene expression of MEF2C in the hippocampus, putamen, thalamus, and frontal white matter. Our study concluded that the MEF2C rs587490 T allele is significantly associated with a reduced risk of ADHD in the Chinese Han population, which provides new insight into the genetic etiology of ADHD.

Global DNA methylation changes in adults with attention deficit-hyperactivity disorder and its comorbidity with bipolar disorder: links with polygenic scores.

Genetic and environmental factors contribute to the etiology of Attention Deficit-Hyperactivity Disorder (ADHD). In this sense, the study of epigenetic mechanisms could contribute to the understanding of the disorder's neurobiology. Global DNA methylation (GMe) evaluated through 5-methylcytosine levels could be a promising epigenetic biomarker to capture long-lasting biological effects in response to environmental and hormonal changes. We conducted the first assessment of GMe levels in subjects with ADHD (n = 394) and its main comorbidities in comparison to populational controls (n = 390). Furthermore, given the high genetic contribution to ADHD (heritability of 80%), polygenic risk scores (PRS) were calculated to verify the genetic contribution to GMe levels in ADHD and the comorbidities associated with GMe levels. The GMe levels observed in patients were lower than controls (P = 1.1e-8), with women being significantly less globally methylated than men (P = 0.002). Regarding comorbidities, the presence of bipolar disorder (BD) among patients with ADHD was associated with higher methylation levels compared to patients with ADHD without BD (P = 0.031). The results did not change when pharmacological treatment was accounted for in the analyses. The ADHD and BD most predictive PRSs were negatively (P = 0.0064) and positively (P = 0.0042) correlated with GMe, respectively. This study is the first to report an association between GMe, ADHD, and its comorbidity with BD and associations between PRSs for specific psychiatric disorders and GMe. Our findings add to previous evidence that GMe may be a relevant piece in the psychiatric disorders' etiological landscape.