Dorsal-to-ventral imbalance in the superior longitudinal fasciculus mediates methylphenidate's effect on beta oscillations in ADHD.

While pharmacological treatment with methylphenidate (MPH) is a first line intervention for ADHD, its mechanisms of action have yet to be elucidated. We here seek to identify the white matter tracts that mediate MPH's effect on beta oscillations. We implemented a double-blind placebo-controlled crossover design, where boys diagnosed with ADHD underwent behavioral and MEG measurements during a spatial attention task while on and off MPH. The results were compared with an age/IQ-matched control group. Estimates of white matter tracts were obtained using diffusion tensor imaging (DTI). Via a stepwise model selection strategy, we identified the fiber tracts (regressors) significantly predicting values of the dependent variables of interest (i.e., oscillatory power, behavioral performance, and clinical symptoms): the anterior thalamic radiation (ATR), the superior longitudinal fasciculus ("parietal endings") (SLFp), and superior longitudinal fasciculus ("temporal endings") (SLFt). ADHD symptoms severity was associated with lower fractional anisotropy (FA) within the ATR. In addition, individuals with relatively higher FA in SLFp compared to SLFt, led to stronger behavioral effects of MPH in the form of faster and more accurate responses. Furthermore, the same parietotemporal FA gradient explained the effects of MPH on beta modulation: subjects with ADHD exhibiting higher FA in SLFp compared to SLFt also displayed greater effects of MPH on beta power during response preparation. Our data suggest that the behavioral deficits and aberrant oscillatory modulations observed in ADHD depend on a possibly detrimental structural connectivity imbalance within the SLF, caused by a diffusivity gradient in favor of parietal rather than temporal, fiber tracts.

Early detection of young children at risk of autism spectrum disorder at well-baby clinics in the Netherlands: Perspectives of preventive care physicians.

LAY ABSTRACT: To improve early detection of autism spectrum disorder in preventive care, a Dutch guideline was developed 5 years ago. The guideline provides preventive care physicians at well-baby clinics action-oriented advice and describes a step-by-step approach for children identified at an increased risk for autism spectrum disorder during general healthcare surveillance. The present qualitative study evaluated adherence to the guideline and studied barriers regarding early detection of autism spectrum disorder at well-baby clinics. Interviews were undertaken with 12 preventive care physicians (one representative per province). It was found that the vast majority of participants did not follow-up general surveillance with an autism spectrum disorder -specific screener as prescribed by the guideline. Six barriers (limited knowledge about autism spectrum disorder symptoms in infant and toddlerhood, professional attitude toward early detection, problems in discussing initial worries with parents, limited use of screening instruments, perceptions toward cultural and language differences and constraints regarding availability of healthcare services) were found. The results of this study highlight the importance of an integrative approach, raising awareness of the benefits regarding early detection of autism spectrum disorder in preventive care, the need of continuous investment in easy and accessible training and active screening, and a closer collaboration between preventive care organizations and autism spectrum disorder experts.

DNA methylation associated with persistent ADHD suggests TARBP1 as novel candidate.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention and/or hyperactivity and impulsivity. ADHD is highly prevalent in childhood and often persists into adulthood. Both genetic variants and environmental factors play a role in the onset and persistence of ADHD, and epigenetic changes, such as DNA methylation are considered as a link for their interplay. To investigate this, we studied DNA methylation in 37 candidate genes by performing targeted bisulfite sequencing of DNA isolated from whole blood of N = 88 individuals diagnosed with adult ADHD and N = 91 unaffected individuals (mean age 34.2 years). Differentially methylated sites were assessed by generalized linear models testing ADHD status and ADHD symptoms, accounting for a methylation-based smoking score, age, sex, and blood cell count. DNA methylation of single sites within DRD4 and KLDR1 was associated with adult ADHD status, and multiple DNA methylation sites within TARBP1 were associated with ADHD symptoms in adulthood and childhood. Awaiting replication, findings of this pilot study point to TARBP1 as a new candidate gene for ADHD symptoms. Our work also stresses the need for research to further examine the effects of environmental factors, such as nicotine exposure, on epigenetic modifications associated with psychiatric traits.

Aggression based genome-wide, glutamatergic, dopaminergic and neuroendocrine polygenic risk scores predict callous-unemotional traits.

Aggression and callous, uncaring, and unemotional (CU) traits are clinically related behavioral constructs caused by genetic and environmental factors. We performed polygenic risk score (PRS) analyses to investigate shared genetic etiology between aggression and these three CU-traits. Furthermore, we studied interactions of PRS with smoking during pregnancy and childhood life events in relation to CU-traits. Summary statistics for the base phenotype were derived from the EAGLE-consortium genome-wide association study of children's aggressive behavior and were used to calculate individual-level genome-wide and gene-set PRS in the NeuroIMAGE target-sample. Target phenotypes were 'callousness', 'uncaring', and 'unemotional' sumscores of the Inventory of Callous-Unemotional traits. A total of 779 subjects and 1,192,414 single-nucleotide polymorphisms were available for PRS-analyses. Gene-sets comprised serotonergic, dopaminergic, glutamatergic, and neuroendocrine signaling pathways. Genome-wide PRS showed evidence of association with uncaring scores (explaining up to 1.59% of variance; self-contained Q = 0.0306, competitive-P = 0.0015). Dopaminergic, glutamatergic, and neuroendocrine PRS showed evidence of association with unemotional scores (explaining up to 1.33, 2.00, and 1.20% of variance respectively; self-contained Q-values 0.037, 0.0115, and 0.0473 respectively, competitive-P-values 0.0029, 0.0002, and 0.0045 respectively). Smoking during pregnancy related to callousness scores while childhood life events related to both callousness and unemotionality. Moreover, dopaminergic PRS appeared to interact with childhood life events in relation to unemotional scores. Our study provides evidence suggesting shared genetic etiology between aggressive behavior and uncaring, and unemotional CU-traits in children. Gene-set PRS confirmed involvement of shared glutamatergic, dopaminergic, and neuroendocrine genetic variation in aggression and CU-traits. Replication of current findings is needed.

Interplay between genome-wide implicated genetic variants and environmental factors related to childhood antisocial behavior in the UK ALSPAC cohort.

We investigated gene-environment (G × E) interactions related to childhood antisocial behavior between polymorphisms implicated by recent genome-wide association studies (GWASs) and two key environmental adversities (maltreatment and smoking during pregnancy) in a large population cohort (ALSPAC). We also studied the MAOA candidate gene and addressed comorbid attention-deficit/hyperactivity disorder (ADHD). ALSPAC is a large, prospective, ethnically homogeneous British cohort. Our outcome consisted of mother-rated conduct disorder symptom scores at age 7;9 years. G × E interactions were tested in a sex-stratified way (α = 0.0031) for four GWAS-implicated variants (for males, rs4714329 and rs9471290; for females, rs2764450 and rs11215217), and a length polymorphism near the MAOA-promoter region. We found that males with rs4714329-GG (P = 0.0015) and rs9471290-AA (P = 0.0001) genotypes were significantly more susceptible to effects of smoking during pregnancy in relation to childhood antisocial behavior. Females with the rs11215217-TC genotype (P = 0.0018) were significantly less susceptible to effects of maltreatment, whereas females with the MAOA-HL genotype (P = 0.0002) were more susceptible to maltreatment effects related to antisocial behavior. After adjustment for comorbid ADHD symptomatology, aforementioned G × E's remained significant, except for rs11215217 × maltreatment, which retained only nominal significance. Genetic variants implicated by recent GWASs of antisocial behavior moderated associations of smoking during pregnancy and maltreatment with childhood antisocial behavior in the general population. While we also found a G × E interaction between the candidate gene MAOA and maltreatment, we were mostly unable to replicate the previous results regarding MAOA-G × E's. Future studies should, in addition to genome-wide implicated variants, consider polygenic and/or multimarker analyses and take into account potential sex stratification.

Substance use and nicotine dependence in persistent, remittent, and late-onset ADHD: a 10-year longitudinal study from childhood to young adulthood.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with substance use disorders (SUD; alcohol and/or drug dependence) and nicotine dependence. This study aims to advance our knowledge about the association between SUD, nicotine dependence, and the course of ADHD (persistent versus remittent ADHD and late-onset ADHD). METHODS: ADHD, SUD, and nicotine dependence were longitudinally assessed (mean age at study entry 11.3 years, mean age at follow-up 21.1 years) using structured psychiatric interviews and multi-informant questionnaires in a subsample of the Dutch part of the International Multicenter ADHD Genetics study. Individuals with persistent ADHD (n = 62), remittent ADHD (n = 12), late-onset ADHD (n = 18; age of onset after 12 years), unaffected siblings (n = 50), and healthy controls (n = 47) were assessed. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated by Cox regression and adjusted for clustered family data, gender, follow-up length, and current age. RESULTS: Individuals with persistent ADHD were at significantly higher risk of development of SUD relative to healthy controls (HR = 4.56, CI 1.17-17.81). In contrast, levels of SUD in those with remittent ADHD were not different from healthy controls (HR = 1.00, CI .07-13.02). ADHD persisters had also higher prevalence rates of nicotine dependence (24.2%) than ADHD remitters (16.7%) and healthy controls (4.3%). A similar pattern was found in initially unaffected siblings who met ADHD criteria at follow-up ("late-onset" ADHD); they had also a higher prevalence of SUD (33%) compared to stable unaffected siblings (20%) and were at significantly increased risk of development of nicotine dependence compared to healthy controls (HR = 13.04, CI 2.08-81.83). CONCLUSIONS: SUD and nicotine dependence are associated with a negative ADHD outcome. Results further emphasize the need for clinicians to comprehensively assess substance use when diagnosing ADHD in adolescents and adults.

Pregnancy risk factors in relation to oppositional-defiant and conduct disorder symptoms in the Avon Longitudinal Study of Parents and Children.

BACKGROUND: Pregnancy factors have been implicated in offspring oppositional-defiant disorder (ODD) and conduct disorder (CD) symptoms. Literature still holds notable limitations, such as studying only a restricted set of pregnancy factors, use of screening questionnaires which assess broadly defined outcome measures, and lack of control for disruptive behavior comorbidity and genetic confounds. We aimed to address these gaps by prospectively studying a broad range of pregnancy factors in relation to both offspring ODD and CD symptomatology in the Avon Longitudinal Study of Parent and Children. METHODS: Outcomes were ODD and CD symptom scores at age 7;9 years using the Development and Well-Being Assessment interview. We analyzed maternal (N ≈ 6300) and teacher ratings (N ≈ 4400) of ODD and CD scores separately using negative binomial regression in multivariable models. Control variables included comorbid attention-deficit/hyperactivity disorder symptoms, ODD or CD symptoms as appropriate, and genetic risk scores based on an independent CD genome-wide association study. RESULTS: Higher ODD symptom scores were linked to paracetamol use (IRR = 1.24 [98.3% confidence interval 1.05-1.47], P = 0.002, teacher ratings) and life events stress (IRR = 1.22 [1.07-1.39], P = 0.002, maternal ratings) during pregnancy. Higher CD symptom scores were linked to maternal smoking (IRR = 1.33 [1.18-1.51], P < 0.001, maternal ratings), life events stress (IRR = 1.24 [1.11-1.38], P < 0.001, maternal ratings) and depressive symptoms (IRR = 1.14 [1.01-1.30], P = 0.006, maternal ratings) during pregnancy. CONCLUSIONS: Common and potentially preventable pregnancy risk factors were independently related to both offspring ODD and CD symptomatology in children from the general population. Future studies should further address genetic confounds and confounding by environmental factors later in life.

Maternal substance use during pregnancy and offspring conduct problems: A meta-analysis.

We conducted meta-analyses of relationships between highly prevalent substance use during pregnancy and offspring conduct disorder problems. In total 36 studies were included. Odds ratios (ORs) were 2.06 (1.67-2.54, 25 studies) for maternal smoking, 2.11 (1.42-3.15, 9 studies) for alcohol use, and 1.29 (0.93-1.81, 3 studies) for cannabis use, while a single study of caffeine use reported no effects. Our meta-analyses support an association between smoking and alcohol use during pregnancy, and offspring conduct problems, yet do not resolve causality issues given potential confounding by genetic factors, gene-environment interactions, and comorbidity such as with attention deficit hyperactivity disorders. Future studies should use genetically sensitive designs to investigate the role of pregnancy substance use in offspring conduct problems and may consider more broadly defined behavioral problems.

Putamen functional connectivity during inhibitory control in smokers and non-smokers.

The putamen has been shown to play a key role in inhibitory control and addiction, and consists of distinct subregions associated with distinct functions. The anterior putamen is thought to be specialized in goal-directed control or response-monitoring in connection with frontal regions, whereas the posterior part is specialized in habitual or automatic responding in connection with sensorimotor regions. The present study is the first to delineate functional networks of the anterior and posterior putamen in a Go-NoGo response inhibition task, and to examine differences between smokers (n = 25) and non-smokers (n = 23) within these networks. Functional connectivity analyses were conducted on fMRI data from a Go-NoGo study, using the generalized form of psychophysiological interaction with anterior and posterior putamen seed regions. In the context of inhibition, the anterior putamen exhibited connectivity with the anterior cingulate cortex (ACC) and precuneus (pFWE < .05), which was in line with previous literature. Conversely, the posterior putamen showed connectivity with regions implicated in sensorimotor processing. When we compared smokers to non-smokers, we did not observe the expected weaker connectivity between the anterior putamen and ACC during inhibition in smokers. Instead, our study revealed stronger inhibition-related connectivity between the anterior putamen and right insula in smokers. This finding highlights the involvement of putamen - insula interactions in addiction and impulse control.

Sustainability of an early detection program for autism spectrum disorder over the course of 8 years.

The importance of early detection of autism spectrum disorder followed by early intervention is increasingly recognized. This quasi-experimental study evaluated the long-term effects of a program for the early detection of autism spectrum disorder (consisting of training of professionals and use of a referral protocol and screening instrument), to determine whether the positive effects on the age at referral were sustained after the program ended while controlling for overall changes in the number of referrals. Before, during, and after the program, the proportion of children referred before 3 years (versus 3-6 years) of age was calculated for children subsequently diagnosed with autism spectrum disorder ( N = 513) or another, non-autism spectrum disorder, condition ( N = 722). The odds of being referred before 3 years of age was higher in children with autism spectrum disorder than in children with another condition during the program than before (3.1, 95% confidence interval: 1.2-7.6) or after (1.7, 95% confidence interval: 1.0-3.0) the program but was not different before versus after the program. Thus, although the program led to earlier referral of children with autism spectrum disorder, after correction for other referrals, the effect was not sustained after the program ended. This study highlights the importance of continued investment in the early detection of autism spectrum disorder.

Effect of tobacco smoking on frontal cortical thickness development: A longitudinal study in a mixed cohort of ADHD-affected and -unaffected youth.

Smoking rates are particularly high during adolescence and young adulthood, when the brain is still undergoing significant developmental changes. Cross-sectional studies have revealed altered brain structure in smokers, such as thinner frontal cortical areas. Attention-deficit/hyperactivity disorder (ADHD) increases the risk of becoming nicotine-dependent, and has also been associated with abnormalities in frontal gray matter structure. The present study examines the relationships between smoking, cortical thickness and ADHD symptoms in a longitudinal design that compares adolescent and young adult smokers (n=44; 35 ADHD-affected) and non-smokers (n=45; 32 ADHD-affected) on frontal cortical thickness. Average frontal cortical thickness was estimated through structural magnetic resonance imaging (MRI) at two time points (mean ages 17.7 and 21.1 years), on average 3.4 years apart. Smokers had a 2.6% thinner frontal cortex than non-smokers and this difference was not explained by ADHD or other confounding factors. The rate of cortical thinning across the 3.4-year MRI measurement interval was similar in the total group of smokers compared to non-smokers. However, speeded thinning did occur in smokers who had started regular smoking more recently, in between the two measurements. These novel regular smokers did not differ significantly from the non-smokers at baseline. This suggests that the thinner frontal cortex was not a predisposing factor but rather a consequence of smoking. Although smokers had more ADHD symptoms overall, smoking did not influence the developmental course of ADHD symptoms.

Age-dependent role of pre- and perinatal factors in interaction with genes on ADHD symptoms across adolescence.

Little is known about the effects of risk factors on attention-deficit/hyperactivity disorder (ADHD) symptom over time. Here, we longitudinally studied the role of candidate genes, pre- and perinatal factors, and their interactions on ADHD symptoms between ages 10 and 18 years. Subjects were part of the general population or clinic-referred cohort of the TRacking Adolescents' Individual Lives Survey (n = 1667). At mean ages of 11.1 (T1), 13.4 (T2), and 16.2 years (T3), ADHD symptoms were assessed with the Child Behavior Checklist. Linear Mixed Models were used to examine the association of candidate genes (i.e., DRD4, DRD2, 5-HTTLPR, COMT, and MAOA), pre- and perinatal factors (i.e., index measure of various pregnancy and delivery complications, maternal smoking, maternal drinking, and low birth weight), and their interactions with ADHD symptoms across adolescence. Pregnancy and delivery complications were associated with a higher level of ADHD symptoms across all time points, but with a significantly declining influence over time (p = 0.006). We found no main effects of the candidate genes on ADHD symptoms throughout adolescence. The simultaneous presence of the low activity MAOA genotype and low birth weight (p < 0.001) and of the 5-HTTLPR LL-allele and respectively pregnancy and delivery complications (p = 0.04) and maternal smoking (p = 0.04) were associated with more ADHD symptoms particularly during early adolescence, and these influences significantly decreased over time. Findings suggest an age-dependent role of gene-environment interactions on ADHD symptoms across adolescence.

Risk factors for comorbid oppositional defiant disorder in attention-deficit/hyperactivity disorder.

Oppositional defiant disorder (ODD) is highly prevalent in attention-deficit/hyperactivity disorder (ADHD). Individuals with both ADHD and ODD (ADHD + ODD) show a considerably worse prognosis compared with individuals with either ADHD or ODD. Therefore, identification of risk factors for ADHD + ODD is essential and may contribute to the development of (early) preventive interventions. Participants were matched for age, gender, and ADHD-subtype (diagnostic groups), and did not differ in IQ. Predictors included pre- and perinatal risk factors (pregnancy duration, birth weight, maternal smoking during pregnancy), transgenerational factors (parental ADHD; parental warmth and criticism in diagnostic groups), and postnatal risk factors (parental socioeconomic status [SES], adverse life events, deviant peer affiliation). Three models were assessed, investigating risk factors for ADHD-only versus controls (N = 86), ADHD + ODD versus controls (N = 86), and ADHD + ODD versus ADHD-only (N = 90). Adverse life events and parental ADHD were risk factors for both ADHD + ODD and ADHD-only, and more adverse life events were an even stronger risk factor for comorbid ODD compared with ADHD-only. For ADHD + ODD, but not ADHD-only, parental criticism, deviant peer affiliation, and parental SES acted as risk factors. Maternal smoking during pregnancy acted as minor risk factor for ADHD-only, while higher birth weight acted as minor risk factor for ADHD + ODD. No effects of age were present. Findings emphasise the importance of these factors in the development of comorbid ODD. The identified risk factors may prove to be essential in preventive interventions for comorbid ODD in ADHD, highlighting the need for parent-focused interventions to take these factors into account.

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects. METHODS: Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. RESULTS: We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. LIMITATIONS: Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. CONCLUSION: While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.

Substance use in individuals with mild to borderline intellectual disability: A comparison between self-report, collateral-report and biomarker analysis.

BACKGROUND AND AIMS: Individuals with mild or borderline intellectual disability (MBID) are at risk of substance use (SU). At present, it is unclear which strategy is the best for assessing SU in individuals with MBID. This study compares three strategies, namely self-report, collateral-report, and biomarker analysis. METHODS AND PROCEDURES: In a sample of 112 participants with MBID from six Dutch facilities providing care to individuals with intellectual disabilities, willingness to participate, SU rates, and agreement between the three strategies were explored. The Substance use and misuse in Intellectual Disability - Questionnaire (SumID-Q; self-report) assesses lifetime use, use in the previous month, and recent use of tobacco, alcohol, cannabis, and stimulants. The Substance use and misuse in Intellectual Disability - Collateral-report questionnaire (SumID-CR; collateral-report) assesses staff members' report of participants' SU over the same reference periods as the SumID-Q. Biomarkers for SU, such as cotinine (metabolite of nicotine), ethanol, tetrahydrocannabinol (THC), and its metabolite THCCOOH, benzoylecgonine (metabolite of cocaine), and amphetamines were assessed in urine, hair, and sweat patches. RESULTS: Willingness to provide biomarker samples was significantly lower compared to willingness to complete the SumID-Q (p<0.001). Most participants reported smoking, drinking alcohol, and using cannabis at least once in their lives, and about a fifth had ever used stimulants. Collateralreported lifetime use was significantly lower. However, self-reported past month and recent SU rates did not differ significantly from the rates from collateral-reports or biomarkers, with the exception of lower alcohol use rates found in biomarker analysis. The agreement between self-report and biomarker analysis was substantial (kappas 0.60-0.89), except for alcohol use (kappa 0.06). Disagreement between SumID-Q and biomarkers concerned mainly over-reporting of the SumID-Q. The agreement between SumID-CR and biomarker analysis was moderate to substantial (kappas 0.48 - 0.88), again with the exception of alcohol (kappa 0.02). CONCLUSIONS AND IMPLICATIONS: In this study, the three strategies that were used to assess SU in individuals with MBID differed significantly in participation rates, but not in SU rates. Several explanations for the better-than-expected performance of self- and collateral-reports are presented. We conclude that for individuals with MBID, self-report combined with collateralreport can be used to assess current SU, and this combination may contribute to collaborative, early intervention efforts to reduce SU and its related harms in this vulnerable group.

Identifying Unique Versus Shared Pre- and Perinatal Risk Factors for ASD and ADHD Using a Simplex-Multiplex Stratification.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. Besides shared genetic factors, pre- and perinatal risk factors (PPFs) may determine if ASD, ADHD, or the combination of both disorders becomes manifest. This study aimed to test shared and unique involvement of PPFs for ASD and ADHD, using an approach that stratifies the sample into affected/unaffected offspring and single-incidence (SPX) versus multi-incidence (MPX) families. Pre- perinatal data based on retrospective parent-report were collected in 288 children (71 % males) from 31 SPX and 59 MPX ASD families, 476 children (65 % males) from 31 SPX and 171 MPX ADHD families, and 408 control children (42 % males). Except for large family size and more firstborns amongst affected offspring, no shared PFFs were identified for ASD and ADHD. PPFs predominantly related to ASD (maternal infections and suboptimal condition at birth) were more often reported in affected than unaffected siblings. PPFs associated with ADHD (low parental age, maternal diseases, smoking and stress) were shared between affected and unaffected siblings. Firstborn-ship was more frequent in SPX than MPX ASD probands. Our results suggest that the co-morbidity of ASD and ADHD is not likely explained by shared PPFs. Instead, PPFs might play a crucial role in the developmental pathways leading up to either disorder. PPFs in ADHD appear to index an increased shared risk, whereas in ASD PPFs possibly have a more determining role in the disorder. SPX-MPX stratification detected possible etiological differences in ASD families, but provided no deeper insight in the role of PPFs in ADHD.

Dopamine and serotonin genetic risk scores predicting substance and nicotine use in attention deficit/hyperactivity disorder.

Individuals with attention deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence. The co-occurrence of ADHD and SUDs/nicotine dependence may in part be mediated by shared genetic liability. Several neurobiological pathways have been implicated in both ADHD and SUDs, including dopamine and serotonin pathways. We hypothesized that variations in dopamine and serotonin neurotransmission genes were involved in the genetic liability to develop SUDs/nicotine dependence in ADHD. The current study included participants with ADHD (n = 280) who were originally part of the Dutch International Multicenter ADHD Genetics study. Participants were aged 5-15 years and attending outpatient clinics at enrollment in the study. Diagnoses of ADHD, SUDs, nicotine dependence, age of first nicotine and substance use, and alcohol use severity were based on semi-structured interviews and questionnaires. Genetic risk scores were created for both serotonergic and dopaminergic risk genes previously shown to be associated with ADHD and SUDs and/or nicotine dependence. The serotonin genetic risk score significantly predicted alcohol use severity. No significant serotonin × dopamine risk score or effect of stimulant medication was found. The current study adds to the literature by providing insight into genetic underpinnings of the co-morbidity of ADHD and SUDs. While the focus of the literature so far has been mostly on dopamine, our study suggests that serotonin may also play a role in the relationship between these disorders.

Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.

Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P=6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P=0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P=7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P=0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P=0.003, permP=0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder.

Substance use disorders in individuals with mild to borderline intellectual disability: current status and future directions.

Knowledge regarding substance use (SU) and substance use disorder (SUD) in individuals with mild to borderline intellectual disabilities (ID) has increased over the last decade, but is still limited. Data on prevalence and risk factors are fragmented, and instruments for screening and assessment and effective treatment interventions are scarce. Also, scientific developments in other fields are insufficiently incorporated in the care for individuals with ID and SUD. In this selective and critical review, we provide an overview of the current status of SU(D) in ID and explore insights on the conceptualisation of SUD from other fields such as addiction medicine and general psychiatry. SU(D) turns out to be a chronic, multifaceted brain disease that is intertwined with other physical, psychiatric and social problems. These insights have implications for practices, policies and future research with regard to the prevalence, screening, assessment and treatment of SUD. We will therefore conclude with recommendations for future research and policy and practice, which may provide a step forward in the care for individuals with ID and SUD.

Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity.

Low birth weight is associated with increased risk for Attention-Deficit/Hyperactivity Disorder (ADHD); however, the etiological underpinnings of this relationship remain unclear. This study investigated if genetic variants in angiogenic, dopaminergic, neurotrophic, kynurenine, and cytokine-related biological pathways moderate the relationship between birth weight and ADHD symptom severity. A total of 398 youth from two multi-site, family-based studies of ADHD were included in the analysis. The sample consisted of 360 ADHD probands, 21 affected siblings, and 17 unaffected siblings. A set of 164 SNPs from 31 candidate genes, representing five biological pathways, were included in our analyses. Birth weight and gestational age data were collected from a state birth registry, medical records, and parent report. Generalized Estimating Equations tested for main effects and interactions between individual SNPs and birth weight centile in predicting ADHD symptom severity. SNPs within neurotrophic (NTRK3) and cytokine genes (CNTFR) were associated with ADHD inattentive symptom severity. There was no main effect of birth weight centile on ADHD symptom severity. SNPs within angiogenic (NRP1 & NRP2), neurotrophic (NTRK1 & NTRK3), cytokine (IL16 & S100B), and kynurenine (CCBL1 & CCBL2) genes moderate the association between birth weight centile and ADHD symptom severity. The SNP main effects and SNP × birth weight centile interactions remained significant after adjusting for multiple testing. Genetic variability in angiogenic, neurotrophic, and inflammatory systems may moderate the association between restricted prenatal growth, a proxy for an adverse prenatal environment, and risk to develop ADHD.