Nudge theory and gambling: a scoping review.

Background: Gambling disorder (GD) is a pressing public health concern with significant societal costs. The recently developed nudge theory, which is rooted in behavioral economics, aims to influence the decision-making behaviors of individuals by implementing changes in the environment. Aim: This scoping review aims to synthesize the literature on nudge theory as it relates to gambling. Methods: This scoping review accords with the Arksey and O'Malley framework, as refined by Levac et al. It includes only articles from peer-reviewed journals that focus, as main themes, on both nudge theory and gambling. The final study selection includes six articles. Results: The scoping review process led to studies explaining how (1) nudges aim to prod people toward healthier gambling choices, fostering the adoption of more responsible gambling practices, and (2) some gambling features, called dark nudges (or sludges), exploit and harm the decision-making processes of people who gamble. Conclusion: This scoping review highlights the fact that many stakeholders are involved in the field of gambling, and that better cooperation between them would promote safer and more responsible gambling practices. Future research is also needed to empirically test nudges to develop a better understanding of their impact on those who gamble.

Correlation of the methylomic signature of smoking during pregnancy with clinical traits in ADHD.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood disorder. Maternal smoking during pregnancy is a replicated environmental risk factor for this disorder. It is also a robust modifier of gene methylation during the prenatal developmental period. In this study, we sought to identify loci differentially methylated by maternal smoking during pregnancy and relate their methylation levels to various behavioural and physical outcomes relevant to ADHD. METHODS: We extracted DNA from blood samples from children diagnosed with ADHD and deeply phenotyped. Genome-wide DNA methylation was assessed using Infinium MethylationEPIC BeadChip. Maternal smoking during pregnancy was self-declared and assessed retrospectively. RESULTS: Our sample included 231 children with ADHD. Statistically significant differences in DNA methylation between children exposed or not to maternal smoking during pregnancy were detected in 3457 CpGs. We kept 30 CpGs with at least 5% of methylation difference between the 2 groups for further analysis. Six genes were associated with varied phenotypes of clinical relevance to ADHD. The levels of DNA methylation in RUNX1 were positively correlated with the CBCL scores, and DNA methylation in MYO1G correlated positively with the score at the Conners rating scale. Methylation level in a CpG located in GFI1 correlated with birthweight, a risk factor for ADHD. Differentially methylated regions were also identified and confirmed the association of RUNX1 methylation levels with the CBCL score. LIMITATIONS: The study has several limitations, including the retrospective recall with self-report of maternal smoking during pregnancy as well as the grouping of individuals of varying age and developmental stage and of both males and females. In addition, the correlation design prevents the building of causation models. CONCLUSION: This study provides evidence for the association between the level of methylation at specific loci and quantitative dimensions highly relevant for ADHD as well as birth weight, a measure that has already been associated with increased risk for ADHD. Our results provide further support to public health educational initiatives to stop maternal smoking during pregnancy.

The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder.

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that deficient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient stratification, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function. Overall, animal and human data concur to suggest that GPR88 signaling should be considered a key factor for diagnostic and treatment of ADHD.

Sex-dependent complex association of TPH2 with multiple dimensions of ADHD.

BACKGROUND: Tryptophan hydroxylase 2 (TPH2) is a key enzyme in the biosynthesis of serotonin in the brain. This study aims to investigate the role of a functional variant in TPH2 (rs17110747) in the pathophysiology of ADHD. This variant has been implicated in mood disorders in recent meta-analysis. This study uses a comprehensive approach that combines association testing and pharmaco-dynamic evaluation of behaviour, in a large sample of children with ADHD (n = 570). METHODS: The association between various ADHD relevant traits and rs17110747 was analyzed using family-based association tests (FBAT). Children were assessed by parents, teachers and research staff under three experimental conditions (EC): baseline, placebo, and methylphenidate using a double-blind placebo-controlled crossover trial. OUTCOMES: FBAT analysis conducted in a sample stratified based on sex of the proband, showed that there was a highly significant overtransmission of the G allele from parents to affected girls. In addition, significant association with several behavioral and cognitive dimensions of ADHD was observed only when the proband was female. Further, girls with the G/G genotype (rs17110747) had greater response to placebo when evaluated by parents. INTERPRETATION: These results suggest that there may be a complex association of TPH2 in the etiology of ADHD, with a sex-specific effect.

Association between COMT methylation and response to treatment in children with ADHD.

BACKGROUND: COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD. METHODS: Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex. RESULTS: Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response. CONCLUSIONS: These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD. TRIAL REGISTRATION: clinicaltrials.gov, number NCT00483106.

Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

OBJECTIVE: The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between genetic and environmental factors, in order to better dissect the aetiology of the disorder. METHOD: We have conducted a clinically-relevant Pharmaco-Behavioural Genetic study in a large group of children with ADHD (~850 families) over the last 15 years. The study includes detailed evaluation of quantitative behavioural and neuropsychological phenotypes, as well as short-term response of these phenotypes to treatment with a fixed dose of methylphenidate (0.5mg/kg in a b.i.d. dose). Specific genetic markers and environmental factors were examined for their association with these dimensions. RESULTS: Here we present results that highlight the importance of examining genetic association with quantitative traits, including those constructs having relevance to Research Domain Criteria (RDoC). Further, we demonstrate that by conducting association analysis in groups of children stratified based on exposure to key environmental exposure (maternal smoking or stress during pregnancy), we are able to increase the sensitivity for finding genes involved in the disorder. CONCLUSION: These results suggest that deep phenotyping and heterogeneity reduction may be imperative in order to uncover the "missing heritability" of the disorder.

OBJECTIF: L'étiologie du trouble de déficit d'attention avec hyperactivité (TDAH) est complexe, puisque des facteurs tant génétiques qu'environnementaux y sont impliqués. L'étude d'association pangénomique du TDAH la plus récente a identifié 12 loci qui présentaient une association significative avec le trouble. Toutefois, comme le soulignent les auteurs, ces loci ne « représentent qu'une infime fraction ¼ du risque de TDAH. Il est suggéré qu'il peut être important de démêler: (1) la complexité clinique du trouble et (2) l'interaction complexe entre les facteurs génétiques et environnementaux, afin de mieux décortiquer l'étiologie du trouble. MÉTHODE: Nous avons mené une étude de génétique pharmaco-comportementale importante sur le plan clinique auprès d'un groupe nombreux d'enfants souffrant du TDAH (~850 familles) au cours des 15 dernières années. L'étude comporte une évaluation détaillée des phénotypes comportementaux et neuropsychologiques quantitatifs, ainsi que la réponse à court terme de ces phénotypes au traitement par dose fixe de méthylphénidate (0,5 mg/kg dans une dose deux fois par jour). Les marqueurs génétiques spécifiques et les facteurs environnementaux ont été examinés relativement à leur association à ces dimensions. RÉSULTATS: Nous présentons ici les résultats qui soulignent l'importance d'examiner l'association génétique avec les traits quantitatifs, y compris ces construits qui ont rapport aux critères du domaine de recherche (RDoC). En outre, nous démontrons qu'en menant une analyse d'association dans des groupes d'enfants stratifiés selon leur exposition à une exposition environnementale principale (le tabagisme maternel ou le stress durant la grossesse), nous sommes capables d'accroître la sensibilité propice à trouver des gènes impliqués dans le trouble. CONCLUSION: Ces résultats suggèrent qu'un phénotypage profond et une réduction de l'hétérogénéité peuvent être impératifs afin de découvrir « l'héritabilité manquante ¼ du trouble.

Acute blood pressure change with methylphenidate is associated with improvement in attention performance in children with ADHD.

This exploratory study aims to determine whether the change in systolic blood pressure (sBP) after acute methylphenidate (MPH) administration (ΔBPMPH) is associated with the neurocognitive response to MPH in the Conners Continuous Performance Test (CPT) in 513 children with ADHD (aged 6 to 12 years old). We noted that higher increases in sBP were associated with larger improvement in CPT performance with MPH. In the univariate regression model, the ΔBPMPH accounted for an additional 2% of the variance in the change in CPT-Overall Index (OI) after controlling for covariates (p < .001). Linear regression analysis also indicated that ΔBPMPH significantly contributed to predict a change in omission errors, reaction time, and reaction time variability (p < .001, p < .01, p = .001, respectively), but not in commission errors or detectability index (d`). Participants with a clinically meaningful sBP increase of at least 5 mmHg (n = 191) improved by 4.8 points on the CPT-OI score (p < .001), compared to an improvement of only 0.6 points for participants whose sBP declined by at least 5 mmHg (n = 121). In conclusion, larger sBP increases after MPH administration were associated with greater enhancement in CPT performance. These results could be useful in informing MPH dosing in clinical practice.

Dissecting genetic cross-talk between ADHD and other neurodevelopmental disorders: Evidence from behavioural, pharmacological and brain imaging investigations.

Several epidemiological and genetic studies have provided evidence of an overlap between neurodevelopmental disorders. However, the details of the etiological pathways remain to be elucidated. In this study, we garnered the findings of previous GWAS, conducted with schizophrenia and bipolar disorder. We conducted an exploratory study to examine the association between these SNPs and quantitative clinical/ behavioural/ cognitive/ structural brain parameters, as well as response to treatment with a fixed dose of methylphenidate, in a relatively large sample of children with ADHD. Family-based association tests were conducted with nine tag SNPs with 602 nuclear families. In addition, structural magnetic resonance imaging (sMRI) was conducted in a subset of children with ADHD (n = 76). Of the 9 tag SNPs examined, rs1602565 showed a significant association with ADHD, several dimensional measures and response to treatment. An association was also observed between rs1006737 (CACNA1C) and performance IQ. In addition, significant reductions in cortical thickness measurements were observed with the risk allele in rs1006737. These results provide preliminary evidence for putative shared genetic vulnerability between childhood ADHD and other neurodevelopmental disorders.

Placebo response and its determinants in children with ADHD across multiple observers and settings: A randomized clinical trial.

This study aims to quantify placebo response (PR) in children with attention deficit hyperactivity disorder (ADHD) as assessed by parents and teachers and to explore some of its determinants. Five hundred and forty children with ADHD (ages 6-12) were recruited to a randomized, double-blind, placebo-controlled crossover trial with methylphenidate. The main outcome variable was Conners' Global Index (CGI), based on assessment of behaviour by parents (CGI-P) and teacher (CGI-T). PR was calculated as the difference between CGI-P/T scores at baseline and placebo week. There was a highly significant PR as assessed by the parents' and teachers' (p < 0.001). The magnitude of PR as assessed by parents was greater (10.57 points) compared to that assessed by teachers (3.93 points). The determinants of PR were different between parents and teachers. For parents, income, marital status, education, maternal smoking during pregnancy, and prior psychostimulant exposure (PPE) showed a significant effect on PR. For teachers, only ethnicity and PPE had an effect. The pattern of PR revealed two distinct profiles that may shed some light on the mechanisms involved in PR. PR in children with ADHD varies depending on the setting of the observations and the evaluator. Several psychosocial factors have been identified as modulators of PR. This is relevant for the design and interpretation of clinical trials and for clinical practice.

Apgar Scores Are Associated with Attention-Deficit/Hyperactivity Disorder Symptom Severity.

OBJECTIVE: Adverse events during pregnancy and delivery have been linked to attention-deficit/hyperactivity disorder (ADHD). Previous studies have investigated Apgar scores, which assess the physical condition of newborns, in relation to the risk of developing ADHD. We propose to go one step further and examine if Apgar scores are associated with ADHD symptom severity in children already diagnosed with ADHD. METHOD: ADHD symptoms severity, while off medication, was compared in 2 groups of children with ADHD: those with low (≤6, n = 52) and those with higher (≥7, n = 400) Apgar scores sequentially recruited from the ADHD clinic. RESULTS: Children with low Apgar at 1 minute after birth had more severe symptoms as assessed by the externalizing scale of the Child Behaviour Checklist, the Conners' Global Index for Parents, and the DSM-IV hyperactivity symptoms count (P = 0.02, <0.01, <0.01, respectively). CONCLUSION: Low 1-minute Apgar scores are associated with a significant increase in ADHD symptom severity. These findings underline the importance of appropriate pregnancy and perinatal care.

The Effect of Maternal Stress during Pregnancy on IQ and ADHD Symptomatology.

OBJECTIVE: Maternal stress during pregnancy (MSDP) has been linked to a decrease in Intelligence Quotient (IQ) in the general population. The purpose of this study is to first examine the association between MSDP and IQ in children with Attention-Deficit/Hyperactivity Disorder (ADHD) and second, to confirm, in a large sample, the link between MSDP and ADHD behavioral symptomatology. METHODS: Four hundred ten children diagnosed with ADHD, ages six to 12, were consecutively recruited from the ADHD clinic and day hospital at the Douglas Institute from 1999 to 2013. IQ was assessed using the WISC III and IV. Symptom severity was evaluated using the Child Behavior Checklist (CBCL) and Connor's Global Index for Parents (CGI-P) and Teachers (CGI-T). RESULTS: No significant effect of MSDP on full scale IQ was observed, but MSDP had a significant effect on CBCL and CGI scores. Elevated MSDP was significantly associated with increased CBCL internalizing scores (ß=4.2, p<.01), CBCL externalizing scores (ß=1.9, p=.04), CGI-P restless-impulsive scores (ß=2.6, p=.01), CGI-P emotional lability scores (ß=3.1, p=.02), and CGI-T restless-impulsive (ß=2.2, p=.05) and emotional lability (ß=3.4, p=.04) scores. MSDP increased the variance explained of ADHD symptomatology even after controlling for various factors (i.e. familial income, parental education, smoking and drinking during pregnancy, gender and age). CONCLUSION: The study demonstrates that in children with ADHD, MSDP does not have an impact on IQ but rather on ADHD symptomatology, highlighting the importance of potentially offering psychological and social support to mothers who experience stress during pregnancy.

OBJECTIF: Le stress maternel durant la grossesse (SMDG) a été lié à une diminution du quotient intellectuel (QI) dans la population générale. Cette étude vise d'abord à examiner l'association entre le SMDG et le QI chez les enfants souffrant du trouble de déficit de l'attention avec hyperactivité (TDAH) et deuxièmement, à confirmer, dans un vaste échantillon, le lien entre le SMDG et la symptomatologie comportementale du TDAH. MÉTHODES: Quatre cent dix enfants de 6 à 12 ans ayant reçu un diagnostic de TDAH ont été consécutivement recrutés dans la clinique du TDAH et l'hôpital de jour de l'Institut Douglas, de 1999 à 2013. Le QI a été évalué à l'aide des échelles WISC III et IV. La gravité des symptômes a été évaluée à l'aide de la liste du comportement de l'enfant (CBCL) et de l'index global de Conner pour les parents (CGI-P) et les enseignants (CGI-T). RÉSULTATS: Aucun effet significatif du SMDG sur le QI global n'a été observé, mais le SMDG avait un effet significatif sur les scores à la CBCL et au CGI. Un SMDG élevé était significativement associé à des scores d'internalisation accrus à la CBCL (ß = 4,2; p<0,01), à des scores d'externalisation à la CBCL (ß = 1,9; p = 0,04), à des scores agité-impulsif au CGI-P (ß = 2,6; p = 0,01), à des scores de labilité émotionnelle au CGI-P (ß = 3,1; p = 0,02), et à des scores agité-impulsif (ß = 2,2; p = 0,05) et de labilité émotionnelle au CGI-T (ß = 3,4; p = 0,04). Le SMDG augmentait la variance expliquée de la symptomatologie du TDAH même après contrôle de facteurs variés (c.-à-d., revenu familial, instruction des parents, tabagisme et consommation d'alcool durant la grossesse, sexe et âge). CONCLUSION: L'étude démontre que chez les enfants souffrant du TDAH, le SMDG n'a pas d'incidence sur le QI mais plutôt sur la symptomatologie du TDAH, ce qui souligne l'importance d'offrir potentiellement un soutien psychologique et social aux mères aux prises avec le stress durant la grossesse.

Increased Risk of Asthma in Children with ADHD: Role of Prematurity and Maternal Stress during Pregnancy.

OBJECTIVE: ADHD and asthma are prevalent conditions in childhood, with complex pathophysiology involving genetic-environmental interplay. The study objective is to examine the prevalence of asthma in our ADHD population and explore factors that may increase the risk of developing asthma in children with ADHD. METHODS: We retrospectively analyzed the presence of maternal stress during pregnancy and history of asthma in 201 children diagnosed with ADHD. RESULTS: Chi-square analysis indicated significant higher presence of asthma in our ADHD sample compared to Quebec children, χ(2)(1, N = 201) = 15.37, P<0.001. Only prematurity and stress during pregnancy significantly predicted asthma in a logistic regression model, χ(2)(2)=23.70, P<0.001, with odds ratios of 10.6 (95% CI: 2.8-39.5) and 3.2 (95% CI: 1.4-7.3), respectively. CONCLUSION: Children with ADHD have a higher prevalence of asthma than the general Quebec pediatric population. Children with ADHD born prematurely and/or those whose mothers experienced stress during pregnancy have a significantly increased risk of developing asthma. The study highlights the importance of potentially offering social and psychological support to mothers who experienced stress during pregnancy and/or are at risk of delivering prematurely.

OBJECTIF: Le TDAH et l'asthme sont des affections prévalentes dans l'enfance, avec une pathophysiologie complexe impliquant une interaction génétique-environnementale. L'étude vise à examiner la prévalence de l'asthme dans notre population TDAH et à explorer les facteurs qui peuvent accroître le risque de développer l'asthme chez les enfants souffrant du TDAH. MÉTHODES: Nous avons analysé rétrospectivement la présence de stress maternel durant la grossesse et les antécédents d'asthme chez 201 enfants ayant reçu un diagnostic de TDAH. RÉSULTATS: L'analyse du chi-carré a indiqué la présence significativement plus élevée d'asthme dans notre échantillon TDAH comparativement aux enfants du Québec, χ2 (1, N = 201) = 15,37; P<0,001. Seuls la prématurité et le stress maternel durant la grossesse prédisaient significativement l'asthme dans un modèle de régression logistique, χ2(2) = 23,70; P<0,001, avec des rapports de cotes de 10,6 (IC à 95% 2,8 à 39,5) et de 3,2 (IC à 95% 1,4 à 7,3), respectivement. CONCLUSION: Les enfants souffrant du TDAH ont une prévalence d'asthme plus élevée que la population pédiatrique générale du Québec. Les enfants souffrant du TDAH nés prématurément et/ou ceux dont les mères ont éprouvé du stress durant la grossesse ont un risque significativement accru de développer l'asthme. L'étude souligne l'importance d'offrir potentiellement un soutien psychologique et social aux mères qui éprouvent du stress durant la grossesse et/ou sont à risque d'accoucher prématurément.

Parental psychopathology in families of children with attention-deficit/hyperactivity disorder and exposed to maternal smoking during pregnancy.

BACKGROUND: Both genetic and environmental factors have been implicated in the etiology of attention-deficit/hyperactivity disorder (ADHD). We had previously suggested that exposure to maternal smoking during pregnancy (MSDP) may be a valid basis for delineating a distinct subtype of ADHD, where children exposed to MSDP present with a more severe clinical picture. Here, we examine the psychopathology of parents in this group, to better understand the etiology of ADHD. METHODS: Using the Family Interview for Genetic Studies in a sample of 514 families of children with ADHD, we collected data pertaining to lifetime parental psychopathology. Families were stratified based on maternal smoking during the complete gestational period. The frequency of different disorders was compared using the χ2 statistic. RESULTS: In the group where mothers smoked during pregnancy, both parents were significantly more likely to have antisocial personality disorder, and problems with alcohol and drug abuse. Mothers had a significantly higher frequency of major depressive disorder (MDD), while fathers showed a trend for both MDD and bipolar disorder. CONCLUSIONS: Based on the pattern of psychopathology in parents of children exposed to MSDP, as well as earlier reports of the severe clinical, behavioral, and cognitive phenotype in these children, combined with the large body of epidemiological evidence, we propose that these children present a distinct subtype of ADHD with comorbid conduct disorder. Furthermore, we propose that MSDP may be a proxy measure to help delineate this subtype.

Association between obesity-related gene FTO and ADHD.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is an etiologically complex heterogeneous behavioral disorder. Several studies have reported that ADHD subjects are more likely to be overweight/obese and that this comorbidity may be due to shared genetic factors. The objective of this study is to explore the association between ADHD and FTO, a gene strongly associated with obesity in genome-wide studies. DESIGN AND METHODS: One tag SNP (single-nucleotide polymorphism, rs8050136, risk allele A) in the FTO gene was selected and its association with ADHD was tested. Family-based association tests (FBATs) were conducted with the categorical diagnosis of ADHD as well as behavioral and cognitive phenotypes related to ADHD. Furthermore, stratified FBAT analyses based on maternal smoking during pregnancy (MSDP) status were conducted. RESULTS: Statistically significant associations were observed between rs8050136 and several of the traits tested in the total sample. These associations were stronger when the analysis was restricted to children who were not exposed to MSDP. CONCLUSIONS: These exploratory results suggest the involvement of the FTO SNP rs8050136 in modulating the risk for ADHD, particularly in those children who were not exposed to MSDP. If confirmed, they may explain, at least in part, the complex links between obesity and ADHD.

Body weight and ADHD: examining the role of self-regulation.

OBJECTIVE: Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex and heterogeneous childhood disorder that often coexists with other psychiatric and somatic disorders. Recently, a link between ADHD and body weight dysregulation has been reported and often interpreted as impaired self-regulation that is shared between the two conditions. The objective of this study is to investigate the relation between body weight/BMI and cognitive, emotional and motor characteristics in children with ADHD. METHODS: 284 ADHD children were stratified by weight status/BMI according to WHO classification and compared with regard to their neurocognitive characteristics, motivational style, and motor profile as assessed by a comprehensive battery of tests. All comparisons were adjusted for demographic characteristics of relevance including, socioeconomic status (SES). RESULTS: Both Obese and overweight ADHD children exhibited significantly lower SES compared to normal weight ADHD children. No significant differences were observed between the three groups with regards to their neurocognitive, emotional and motor profile. CONCLUSIONS: Our findings provide evidence that differences in weight/BMI are not accounted for by cognitive, motivational and motor profiles. Socio-economic characteristics are strongly associated with overweight and obesity in ADHD children and may inform strategies aimed at promoting healthier weight.

Genetic evidence for the association of the hypothalamic-pituitary-adrenal (HPA) axis with ADHD and methylphenidate treatment response.

Exposure to stressors results in a spectrum of autonomic, endocrine, and behavioral responses. A key pathway in this response to stress is the hypothalamic-pituitary-adrenal (HPA) axis, which results in a transient increase in circulating cortisol, which exerts its effects through the two related ligand-activated transcription factors: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Genetic polymorphisms in these receptors have been shown to influence HPA axis reactivity, and chronic dysregulation of the HPA axis has been associated with the development of several psychiatric disorders. The objective of the study was to test the association between four functional polymorphisms in NR3C1 (encoding GR: ER22/23EK-rs6189, N363S-rs6195, BclI-rs41423247, A3669G-rs6198) and two in NR3C2 (encoding MR: 215G/C-rs2070951, I180 V-rs5522) with childhood ADHD. Family-based association tests (FBAT) were conducted with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, as well as with treatment response assessed in a 2-week, double-blind, placebo-controlled trial with methylphenidate. A specific haplotype (G:A:G:G; ER22/23EK- N363S- BclI- A3669G) of NR3C1 showed a significant association with behaviors related to ADHD (particularly thought and attention problems, aggressive behavior), comorbidity with oppositional defiant disorder, and executive function domains. An association was also observed with treatment response (assessed by the Conners'-Teachers and Restricted Academic Situation Scale). In contrast, MR gene polymorphisms were not associated with any of the variables tested. To the best of our knowledge, this is the first report showing an association between functional polymorphisms in NR3C1 and ADHD, providing genetic evidence for involvement of the HPA axis in the disorder and treatment response.

Refining psychiatric phenotypes for response to treatment: contribution of LPHN3 in ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder characterized by inappropriate levels of attention, hyperactivity, and impulsivity. Although a strong genetic component to the disorder has been established, the molecular genetic underpinnings of this disorder remain elusive. Recently, several studies have reported an association between polymorphisms within the latrophilin 3 gene (LPHN3) and ADHD. Interestingly, the same single-nucleotide polymorphism conferring susceptibility to ADHD has also been found to predict efficacy of stimulant medication in children. The main objectives of the current article are: (i) To tackle the phenotype heterogeneity issue in ADHD by defining an objective and quantitative measure of response to treatment in a sample of ADHD children based on a hand held automatic device (Actiwatch) and (ii) to use this measure to reproduce for the first time the association between LPHN3 variants and response to methylphenidate (MPH) using a double-blind, placebo-controlled crossover experimental design. The results of our study confirm the hypothesis that LPHN3 is associated with response to MPH in ADHD children. Although this will require further validation, our work suggests that the use of an objective measure of response to treatment, such as the change in the child's motor activity measured by Actiwatch, has the potential to uncover genetic association signals that in some conditions might not be obtained using more subjective measures, such as the clinical consensus rating, for example.

LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association was reported between ADHD and LPHN3 (which codes for latrophilin 3), and replicated in independent samples. METHODS: We have examined the association between tag single nucleotide polymorphisms (SNPs) in LPHN3 within the region previously implicated in ADHD. Family based association tests (FBAT) were conducted (n = 380 families) with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, and response to treatment (given a fixed dose of methylphenidate, 0.5 mg/day). Stratified FBAT analyses, based on maternal smoking and stress during pregnancy, was conducted. RESULTS: Whereas limited association was observed in the total sample, highly significant interaction between four LPHN3 tag SNPs (rs6551665, rs1947274, rs6858066, rs2345039) and maternal stress during pregnancy was noted. Analysis conducted in the sub-group of mothers exposed to minimal stress during pregnancy showed significant associations with ADHD, behavioral and cognitive dimensions related to ADHD, as well as treatment response. Although extensive association was observed with the candidate SNPs, the findings are partially inconsistent with previously published results with the opposite alleles over-transmitted in these studies. CONCLUSIONS: These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD.

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype.

BACKGROUND: Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD. METHODS: Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT. RESULTS: A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5' region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2. LIMITATIONS: The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype. CONCLUSION: The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.

Maternal Stress during Pregnancy, ADHD Symptomatology in Children and Genotype: Gene-Environment Interaction.

OBJECTIVE: Case control studies suggest a relationship between maternal stress during pregnancy and childhood ADHD. However, maternal smoking, parenting style and parental psychiatric disorder are possible confounding factors. Our objective was to control for these factors by using an intra-familial design, and investigate gene-environment interactions. METHODS: One hundred forty two children, ages 6 to 12, (71 with ADHD, and their 71 non-ADHD siblings) participated in the intra-familial study design. A larger sample of ADHD children (N=305) was genotyped for DAT1 and DRD4 to examine gene-environment interactions. Symptom severity was evaluated using the Child Behavior Checklist (CBCL) and the Conners' Global Index for Parents (CGI-P). The Kinney Medical and Gynecological Questionnaire was used to report stressful events during pregnancies. RESULTS: LOGISTIC REGRESSION INDICATED THAT MOTHERS WERE MORE LIKELY TO HAVE EXPERIENCED HIGH STRESS DURING PREGNANCY OF THEIR ADHD CHILD COMPARED TO THAT OF THE UNAFFECTED SIBLING (OR: 6.3, p=.01). In the larger sample, DRD4 7/7 genotype was associated with increased symptom severity in the high stress pregnancy (p=.01). CONCLUSIONS: Maternal stress during pregnancy was associated with the development of ADHD symptomatology after controlling for family history of ADHD and other environmental factors. This association could partly be mediated through the DRD4 genotype.