Latent class analysis to characterize neonatal risk for neurodevelopmental differences.

BACKGROUND: Neonatal risk factors, such as preterm birth and low birth weight, have been robustly linked to neurodevelopmental deficits, yet it is still unclear why some infants born preterm and/or low birth weight experience neurodevelopmental difficulties while others do not. The current study investigated this heterogeneity in neurodevelopmental abilities by examining additional neonatal morbidities as risk factors, utilizing latent class analysis to classify neonates into groups based on similar neonatal risk factors, and including neonates from the full spectrum of gestational age. METHODS: Neonates who received neonatal care at an academic public hospital during an almost 10-year period (n = 19,951) were included in the latent class analysis, and 21 neonatal indicators of health were used. Neonatal class, sex, and the interaction between neonatal class and sex were used to examine differences in neurodevelopment at 18 months of age in a typically developing population. RESULTS: The best fitting model included five infant classes: healthy, hypoxic, critically ill, minorly ill, and complicated delivery. Scores on the parent-rated neurodevelopmental measure differed by class such that infants in the critically ill, minorly ill, and complicated delivery classes had lower scores. There was no main effect of sex on the neurodevelopmental measure scores, but the interaction between sex and neonatal class was significant for three out of five neurodevelopmental domains. CONCLUSIONS: The current study extends the understanding of risk factors in neurodevelopment by including several neonatal medical conditions that are often overlooked and by using a person-centered, as opposed to variable-centered, approach. Future work should continue to examine risk factors, such as maternal health during pregnancy and medical interventions for newborns, in relation to neonatal risks and neurodevelopment by using a person-centered approach.

Neuropsychological performance measures as intermediate phenotypes for attention-deficit/hyperactivity disorder: A multiple mediation analysis.

Genetic influences on dopaminergic neurotransmission have been implicated in attention-deficit hyperactivity disorder (ADHD) and are theorized to impact cognitive functioning via alterations in frontal-striatal circuitry. Neuropsychological functioning has been proposed to account for the potential associations between dopamine candidate genes and ADHD. However, to date, this mediation hypothesis has not been directly tested. Participants were 498 youth ages 6-17 years (mean M = 10.8 years, SD = 2.4 years, 55.0% male). All youth completed a multistage, multiple-informant assessment procedure to identify ADHD and non-ADHD cases, as well as a comprehensive neuropsychological battery. Youth provided a saliva sample for DNA analyses; the 480 base pair variable number of tandem repeat polymorphism of the dopamine active transporter 1 gene (DAT1) and the 120 base pair promoter polymorphism of the dopamine receptor D4 gene (DRD4) were genotyped. Multiple mediation analysis revealed significant indirect associations between DAT1 genotype and inattention, hyperactivity-impulsivity, and oppositionality, with specific indirect effects through response inhibition. The results highlight the role of neurocognitive task performance, particularly response inhibition, as a potential intermediate phenotype for ADHD, further elucidating the relationship between genetic polymorphisms and externalizing psychopathology.

Variation in an Iron Metabolism Gene Moderates the Association Between Blood Lead Levels and Attention-Deficit/Hyperactivity Disorder in Children.

Although attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental condition, there is also considerable scientific and public interest in environmental modulators of its etiology. Exposure to neurotoxins is one potential source of perturbation of neural, and hence psychological, development. Exposure to lead in particular has been widely investigated and is correlated with neurodevelopmental outcomes, including ADHD. To investigate whether this effect is likely to be causal, we used a Mendelian randomization design with a functional gene variant. In a case-control study, we examined the association between ADHD symptoms in children and blood lead level as moderated by variants in the hemochromatosis (HFE) gene. The HFE gene regulates iron uptake and secondarily modulates lead metabolism. Statistical moderation was observed: The magnitude of the association of blood lead with symptoms of ADHD was altered by functional HFE genotype, which is consistent with a causal hypothesis.

Risky bicycling behavior among youth with and without attention-deficit hyperactivity disorder.

BACKGROUND: Injury risk from car-bicycle collisions is particularly high among youth with attention-deficit hyperactivity disorder (ADHD). Here, we capitalized on advances in virtual environment technology to safely and systematically examine road-crossing behavior among child cyclists with and without ADHD. METHODS: Sixty-three youth (26 with ADHD, 37 non-ADHD controls) ages 10-14 years crossed 12 intersections with continuous cross-traffic while riding a high-fidelity bicycling simulator. Traffic density (i.e., temporal gaps between vehicles) was manipulated to examine the impact of varying traffic density on behavioral indices of road crossing, including gap selection, timing of entry into the roadway, time to spare when exiting the roadway, and close calls with oncoming cars. In addition, parents filled out questionnaires assessing their child's ADHD symptomatology, temperamental characteristics, bicycling experience, and injury history. RESULTS: ADHD youth largely chose the same size gaps as non-ADHD youth, although ADHD youth were more likely to select smaller gap sizes following exposure to high-density traffic. In addition, youth with ADHD demonstrated poorer movement timing when entering the intersection, resulting in less time to spare when exiting the roadway. Hyperactivity-impulsivity symptoms were specifically associated with selection of smaller gaps, whereas timing deficits were specifically associated with inattention and inhibitory control. CONCLUSION: Findings highlight two related yet potentially dissociable mechanisms that may influence injury risk among youth with ADHD and provide a foundation for development of injury prevention strategies.

Does 5HTTLPR Genotype Moderate the Association of Family Environment With Child Attention-Deficit Hyperactivity Disorder Symptomatology?

Problematic family dynamics are common among youth with attention-deficit hyperactivity disorder (ADHD). Multiple mechanisms, including diathesis-stress (vulnerability) and differential susceptibility Gene × Environment interaction effects (G × E), have been proposed to account for this association. G × E effects for ADHD were examined via interactions between a genetic marker hypothesized to influence sensitivity to the environment (the promoter polymorphism of the serotonin transporter gene -5HTTLPR) and family conflict and cohesion in predicting ADHD symptoms. There were 498 youth ages 6-17 years (251 ADHD, 213 non-ADHD) and their parents who completed a multistage, multi-informant assessment (including parent and youth reports on the Family Environment Scale), and saliva sample collection for genotyping. Linear regression analyses examined interactions between 5HTTLPR genotype and the Family Environment Scale scales of conflict and cohesion reported by parent and child. Criteria laid out by Roisman et al. ( 2012 ) were applied to evaluate diathesis stress versus differential susceptibility G × E mechanisms. Results demonstrated interactions between 5HTTLPR genotype and both conflict and cohesion in predicting inattention but not hyperactivity-impulsivity. Both interactions were highly consistent with differential susceptibility models of G × E effects. 5HTTLPR genotype appeared to moderate the relationship between family conflict/cohesion and inattentive symptoms. Interactions highlight the role of 5HTTLPR genotype as a potential marker of environmental sensitivity and provide support for differential susceptibility models of G × E effects for ADHD.

Parental involvement moderates etiological influences on attention deficit hyperactivity disorder behaviors in child twins.

Although few would now contest the presence of Gene × Environment (G × E) effects in the development of child psychopathology, it remains unclear how these effects manifest themselves. Alternative G × E models have been proposed (i.e., diathesis-stress, differential susceptibility, bioecological), each of which has notably different implications for etiology. Child twin studies present a powerful tool for discriminating between these models. The current study examined whether and how parental involvement moderated etiological influences on attention deficit hyperactivity disorder (ADHD) within 500 twin pairs aged 6-11 years. Results indicated moderation of genetic and nonshared environmental contributions to ADHD by parental involvement, and moreover, suggested both differential susceptibility and bioecological models of G × E. Results highlight the utility of child twin samples in testing different manifestations of G × E effects.

Distinct neuropsychological subgroups in typically developing youth inform heterogeneity in children with ADHD.

Research and clinical investigations in psychiatry largely rely on the de facto assumption that the diagnostic categories identified in the Diagnostic and Statistical Manual (DSM) represent homogeneous syndromes. However, the mechanistic heterogeneity that potentially underlies the existing classification scheme might limit discovery of etiology for most developmental psychiatric disorders. Another, perhaps less palpable, reality may also be interfering with progress-heterogeneity in typically developing populations. In this report we attempt to clarify neuropsychological heterogeneity in a large dataset of typically developing youth and youth with attention deficit/hyperactivity disorder (ADHD), using graph theory and community detection. We sought to determine whether data-driven neuropsychological subtypes could be discerned in children with and without the disorder. Because individual classification is the sine qua non for eventual clinical translation, we also apply support vector machine-based multivariate pattern analysis to identify how well ADHD status in individual children can be identified as defined by the community detection delineated subtypes. The analysis yielded several unique, but similar subtypes across both populations. Just as importantly, comparing typically developing children with ADHD children within each of these distinct subgroups increased diagnostic accuracy. Two important principles were identified that have the potential to advance our understanding of typical development and developmental neuropsychiatric disorders. The first tenet suggests that typically developing children can be classified into distinct neuropsychological subgroups with high precision. The second tenet proposes that some of the heterogeneity in individuals with ADHD might be "nested" in this normal variation.

Youth Polygenic Scores, Youth ADHD Symptoms, and Parenting Dimensions: An Evocative Gene-Environment Correlation Study.

Parenting practices and parental symptoms of attention-deficit/hyperactivity disorder (ADHD) have been linked to severity and course of youth ADHD. However, genetically influenced behaviors related to ADHD in youth may also influence parenting behaviors. Polygenic scores (PGS) have been widely used to quantify genetic vulnerability for ADHD but has rarely been used to examine gene-environment correlation effects. The current study examined the direct effects of youth ADHD PGS and its evocative effects on parenting behaviors via youth ADHD symptoms. 803 youth aged 6-18 years (58.5% male) completed a multistage, multi-informant assessment that included measures of parenting practices and youth and parental ADHD symptoms. A mediation model was used to evaluate direct and evocative effects. Furthermore, we examined if these evocative effects remain after controlling for parental ADHD symptoms. Sensitivity analyses across age, sex, and socioeconomic status (SES) as well as restricting ancestry groups to European only ancestry were also conducted. Results indicated that youth ADHD PGS reliably predicted youth ADHD symptoms across all models (ßs ranging from 0.18 to 0.26), including across age, sex, and SES and held even with ancestry restricted to the largest group (northern European). Evocative effects emerged such that higher youth PGS significantly predicted more youth ADHD symptoms, which in turn, significantly predicted lower levels of parental involvement and higher levels of poor supervision/monitoring and inconsistent discipline. These effects remained after controlling for parent ADHD symptoms.

The Oregon ADHD-1000: A new longitudinal data resource enriched for clinical cases and multiple levels of analysis.

The fields of developmental psychopathology, developmental neuroscience, and behavioral genetics are increasingly moving toward a data sharing model to improve reproducibility, robustness, and generalizability of findings. This approach is particularly critical for understanding attention-deficit/hyperactivity disorder (ADHD), which has unique public health importance given its early onset, high prevalence, individual variability, and causal association with co-occurring and later developing problems. A further priority concerns multi-disciplinary/multi-method datasets that can span different units of analysis. Here, we describe a public dataset using a case-control design for ADHD that includes: multi-method, multi-measure, multi-informant, multi-trait data, and multi-clinician evaluation and phenotyping. It spans > 12 years of annual follow-up with a lag longitudinal design allowing age-based analyses spanning age 7-19 + years with a full age range from 7 to 21. Measures span genetic and epigenetic (DNA methylation) array data; EEG, functional and structural MRI neuroimaging; and psychophysiological, psychosocial, clinical and functional outcomes data. The resource also benefits from an autism spectrum disorder add-on cohort and a cross sectional case-control ADHD cohort from a different geographical region for replication and generalizability. Datasets allowing for integration from genes to nervous system to behavior represent the "next generation" of researchable cohorts for ADHD and developmental psychopathology.

Sluggish Cognitive Tempo as a Transdiagnostic Link Between Adult ADHD and Internalizing Symptoms.

Objective: Although absent from traditional diagnostic nosologies, Sluggish Cognitive Tempo (SCT) may have transdiagnostic utility given its robust associations with ADHD and internalizing symptoms as well as with cognitive impairments common to these conditions. Within-person variation in SCT symptoms may also serve to link ADHD, cognitive deficits, and internalizing psychopathology, however, few studies have utilized intensive longitudinal designs to probe within-person variation in SCT and its links to cognitive deficits and psychopathology. Method: Ecological Momentary Assessment was used to measure between and within-person variance in SCT 4 times per day across 7 days (28 time-points) in 158 college students (approximately 51% with elevated ADHD and/or internalizing symptoms). Participants also completed ratings of current and childhood ADHD symptoms, cognitive function and internalizing psychopathology. Parameters derived from longitudinal multilevel models indexing between and within person variation in SCT were examined as mediators of the associations between (1) ADHD and internalizing symptoms and (2) self-reported cognitive functioning and internalizing symptoms. Results: Results indicated that between-person differences in SCT, but not within-person variability, linked current and childhood ADHD and internalizing symptoms. Similarly, problems in time-management and organization influenced internalizing psychopathology via between-person differences in SCT. Conclusion: Results found that SCT may be a transdiagnostic link bridging mental health comorbidities, cognitive dysfunction, and internalizing psychopathology.

A Meta-Analytic Review of Emotion Regulation Focused Psychosocial Interventions for Adolescents.

Emotion regulation (ER) is the ability to monitor, evaluate, and modify one's emotional responses to be appropriate for environmental demands. Poor ER has been considered a transdiagnostic risk factor for a range of internalizing and externalizing disorders and overall decreased well-being in adolescents. A range of evidence-based interventions exist which may improve ER. However, much of the intervention research to date does not include a measure of ER to assess change pre and post treatment, with limited information about the efficacy of these interventions in youth across a range of sample types. There is a clear need for a comprehensive review of the literature examining ER-focused interventions in adolescents with a wide range of presenting disorders. A literature search was originally conducted in January 2020 and an updated search was conducted in February 2021 which elicited 1245 articles, of which 605 were duplicates and were removed. Abstracts of the remaining 640 articles were screened with 121 articles being reviewed in full. Of note, 16 additional articles were identified through references and other sources during this process and were also included in the full review. Of the 137 articles reviewed in full, 41 studies were ultimately included in the present review. The present paper provides a descriptive review of intervention approaches and findings from community prevention programs, programs for war-affected youth, programs for clinical populations, and programs for incarcerated and delinquent adolescents. The overall pooled effect was significantly different from zero based on the pre/post effects [Hedge's g = 0.29, 95% CI (0.22, 0.36)] and the intervention/control effects [Hedge's g = 0.19, 95% CI (0.06-0.32)]. Although neither sex nor age significantly accounted for heterogeneity in effect sizes, there were significant findings for population type (clinical vs. community), with community samples having significantly lower effect sizes on average. Impacts of the different ER measures used and significant methodological variability (e.g., use of control groups, length of intervention) across included studies are discussed. Implications and suggestions for future research are reviewed, specifically, that additional understanding of moderators of effects are needed and that measures used to assess change in ER, both dysregulation and adaptive skill use, may need to more directly align with the intervention's focus and the strategies taught as part of the intervention.

Telomere Length and ADHD Symptoms in Young Adults.

Objective: Previous research examining telomeres in individuals with neuropsychiatric disorders shows that greater illness, symptoms, or cognitive impairment are linked with shorter telomeres. However, the relationships of telomere length and neuropsychological processes or psychiatric symptoms are not understood in individuals with Attention Deficit/Hyperactivity Disorder (ADHD). Method: 390 young adults with and without ADHD completed a multi-informant diagnostic assessment and neuropsychological testing battery. Participant DNA was isolated from saliva samples, and telomere length was determined using qPCR. Results: Linear regression models demonstrated the only significant association to survive correction for multiple testing was for childhood hyperactivity-impulsivity symptoms and longer telomere length. Conclusion: Contrary to expectations, longer telomere length in young adults was associated only with childhood ADHD symptoms, particularly hyperactivity-impulsivity, in this sample. These findings are an important demonstration that the neuropsychological deficits and symptoms experienced by individuals diagnosed with ADHD during adulthood may not be negatively associated with telomere length.

Evaluating the Viability of Neurocognition as a Transdiagnostic Construct Using Both Latent Variable Models and Network Analysis.

The relational structure of psychological symptoms and disorders is of crucial importance to mechanistic and causal research. Methodologically, factor analytic approaches (latent variable modeling) and network analyses are two dominant approaches. Amidst some debate about their relative merits, use of both methods simultaneously in the same data set has rarely been reported in child or adolescent psychopathology. A second issue is that the nosological structure can be enriched by inclusion of transdiagnostic constructs, such as neurocognition (e.g., executive functions and other processes). These cut across traditional diagnostic boundaries and are rarely included even though they can help map the mechanistic architecture of psychopathology. Using a sample enriched for ADHD (n = 498 youth ages 6 to 17 years; M = 10.8 years, SD = 2.3 years, 55% male), both approaches were used in two ways: (a) to model symptom structure and (b) to model seven neurocognitive domains hypothesized as important transdiagnostic features in ADHD and associated disorders. The structure of psychopathology domains was similar across statistical approaches with internalizing, externalizing, and neurocognitive performance clusters. Neurocognition remained a distinct domain according to both methods, showing small to moderate associations with internalizing and externalizing domains in latent variable models and high connectivity in network analyses. Overall, the latent variable and network approaches yielded more convergent than discriminant findings, suggesting that both may be complementary tools for evaluating the utility of transdiagnostic constructs for psychopathology research.

Barkley Deficits in Executive Functioning Scale (BDEFS): Validation in a Large Multisite College Sample.

Despite the importance of daily life executive functioning (EF) for college students' success, few measures exist that have been validated in college students specifically. This study examined the factor structure of the Barkley Deficits in Executive Functioning Scale (BDEFS) in college students. Participants were 1,311 students (ages 18-28 years, 65% female) from five universities in the United States. Additionally, the study examined invariance across sex, age, and attention-deficit/hyperactivity disorder symptoms. Exploratory structural equation modeling provided strong support for the BDEFS five-factor structure though some items had high cross-loadings on multiple factors. Findings generally supported invariance across sex and age; however, loadings, thresholds, and factor means differed based on attention-deficit/hyperactivity disorder symptoms. Stronger support for invariance across sex emerged for a reduced item version that eliminated cross-loading items. Overall, findings provide support for the validity and utility of the BDEFS in college students.

Multigroup multilevel structure of the child and parent versions of the Positive and Negative Affect Schedule (PANAS) in adolescents with and without ADHD.

The Positive and Negative Affect Schedule (PANAS) has been widely used to assess affect expression. Shortened and adolescent versions of the measure have been created, such as the 10-item PANAS for Children (PANAS-C). However, affect expression often involves substantial intraindividual variability, and no research has examined within-person differences using the 10-item PANAS-C. Moreover, intraindividual variability is a key characteristic of attention-deficit hyperactivity disorder (ADHD), and emotion dysregulation is a key feature of ADHD. The present study examined the factor structure of the 10-item PANAS-C in a sample of adolescents (Mage = 13.17 years) with (n = 156) and without (n = 139) ADHD. A 3-factor (Positive Affect, Fear, Distress) within and a 2-factor (Positive Affect, Negative Affect) between model was found to be best fitting using both parent and adolescent reports. The model demonstrated configural invariance for the adolescent report and scalar invariance for the parent report. These results support the multidimensionality of negative affect in youth with ADHD, even when assessed via the short-version PANAS-C. In future work, it will be important to consider the implications of more discrete types of negative affect expression (fear and distress) found across time at the individual level for assessment and intervention practice. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The role of neurocognitive tests in the assessment of adult attention-deficit/hyperactivity disorder.

Despite widespread recognition that attention-deficit/hyperactivity disorder (ADHD) is a lifelong neurodevelopmental disorder, optimal methods of diagnosis among adults remain elusive. Substantial overlap between ADHD symptoms and cognitive symptoms of other mental health conditions, such as depression and anxiety, and concerns about validity in symptom reporting have made the use of neuropsychological tests in ADHD diagnostic assessment appealing. However, past work exploring the potential diagnostic utility of neuropsychological tests among adults has often relied on a relatively small subset of tests, has failed to include symptom and performance validity measures, and often does not include comparison groups of participants with commonly comorbid disorders, such as depression. The current study examined the utility of an extensive neuropsychological measure battery for diagnosing ADHD among adults. Two hundred forty-six participants (109 ADHD, 52 depressed, 85 nondisordered controls) completed a multistage screening and assessment process, which included a clinical interview, self, and informant report on behavior rating scales, performance and symptom validity measures, and an extensive neuropsychological testing battery. Results indicated that measures of working memory, sustained attention, response speed, and variability best discriminated ADHD and non-ADHD participants. While single test measures provided performed poorly in identifying ADHD participants, analyses revealed that a combined approach using self and informant symptom ratings, positive family history of ADHD, and a reaction time (RT) variability measure correctly classified 87% of cases. Findings suggest that neuropsychological test measures used in conjunction with other clinical assessments may enhance prediction of adult ADHD diagnoses. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A meta-analytic review of the association between cortisol reactivity in response to a stressor and attention-deficit hyperactivity disorder.

A substantial literature suggests that abnormal cortisol reactivity may be a vulnerability for deleterious mental health outcomes, including ADHD. ADHD has been linked with difficulty in emotion regulation and increased risk of experiencing stressors, both of which may be related to psychobiological abnormalities (e.g., abnormal cortisol reactivity). Research has been mixed regarding the association between cortisol reactivity and ADHD. Therefore, the present meta-analytic review (k = 12) sought to quantify this association and review the relevant methodological issues and theoretical implications of this area of research. Overall, no effect was found between cortisol reactivity and ADHD (r = 0), although significant heterogeneity in the analyses suggested that there might be moderators of this association, if one does exist. Results highlight the importance of addressing limitations of the current literature on cortisol reactivity and ADHD and exploring additional indices of emotion regulation that may be associated with ADHD. Implications for future research efforts are discussed.

Sluggish Cognitive Tempo Symptoms Contribute to Heterogeneity in Adult Attention-Deficit Hyperactivity Disorder.

Attention-deficit hyperactivity disorder (ADHD) persists into adulthood in over 50% of cases, although its associated symptom profiles, comorbid problems, and neuropsychological deficits change substantially across development. Sluggish cognitive tempo (SCT) symptoms may contribute to associations between ADHD and comorbid problems and may partially explain the substantial heterogeneity observed in its correlates. 349 adults aged 18-38 years (M = 23.2, SD = 4.5, 54.7% male, 61.03% with ADHD) completed a multi-informant diagnostic procedure and a comprehensive neuropsychological battery. Adults with ADHD (n = 213) were retained for analyses. Latent class analyses (LCA) revealed three profiles of SCT symptoms among those with ADHD, which we classified as minimal, moderate, or severe SCT. Multiple analysis of covariance (MANCOVA) revealed significant differences among these profiles, which remained when controlling for persistence of ADHD symptoms and sex. In general, adults with ADHD combined with SCT symptoms (moderate and severe) had significantly more symptoms of anxiety, depression, and persistent inattention, and had more severe professional and relational impairment compared to ADHD adults without SCT. Compared to those with moderate or minimal SCT symptoms, the severe SCT group had the most symptoms of depression and internalizing disorders, and the most impairment in the domain of daily responsibility. No significant differences based on externalizing symptoms emerged when controlling for sex and persistence of inattention symptoms, suggesting the moderate and severe SCT groups do not simply reflect more symptoms. Moreover, follow-up mediation analyses revealed that SCT might at least partially explain the heterogeneity in ADHD. Findings have implications for refinement of etiological conceptualization, assessment methods, and intervention strategies.

A Meta-Analysis of the Association Between Birth Weight and Attention Deficit Hyperactivity Disorder.

A large body of work has investigated the association between birth weight and ADHD and has resulted in mixed findings with regard to the direction and magnitude of this association. Despite the vast amount of research on this topic, a comprehensive and systematic quantification of the association between birth weight and ADHD has yet to be undertaken. A meta-analysis of 88 unique studies (N = 4,645,482) was conducted to quantify the overall effect size of birth weight on ADHD symptoms. Several variables were examined as moderators that may contribute to systematic variation in effect sizes. Overall, birth weight was found to have a small, but significant, association with ADHD symptoms such that individuals born at lower birth weights manifested greater symptoms of ADHD (r = -0.15). Sample type, mean birth weight of the sample, geographic region, the informant of ADHD symptoms, ADHD symptom measurement method, and race were all found to contribute significantly to heterogeneity in effect sizes. Notably, several early life risk factors previously found to be associated with both ADHD and birth weight, gestational age and prenatal smoking exposure, were not found to contribute to heterogeneity in effect sizes. The findings of the current analyses align with the growing recognition that early life adversity contributes to neurodevelopmental difficulties, and the findings highlight the importance of a better understanding of the mechanisms underlying the association between early life risk factors and adverse neurodevelopmental sequela, such as that observed in ADHD.

DRD4 Variants Moderate the Impact of Parental Characteristics on Child Attention-Deficit Hyperactivity Disorder: Exploratory Evidence from a Multiplex Family Design.

Parental ADHD symptomatology and related impairments have been robustly associated with youth ADHD across decades of work. Notably, these factors may impede typical development of child self-regulation capabilities through both neurobiological and interpersonal processes. High heritability of estimates for the disorder further suggest that these effects are likely genetically-mediated, at least in part. Variation within the dopamine D4 receptor gene (DRD4) has been shown to moderate parental influences on youth ADHD. Use of a multiplex family design (i.e., samples of families that included multiple affected members) may facilitate identification of additional gene variants of interest and advance understanding of gene-environment interplay in regard to parenting. Thirty multiplex families consisting of 114 individuals (66 youth, 48 parents) completed a multi-stage, multi-informant diagnostic and neurocognitive assessment, measures of parenting, and provided saliva samples for DNA analyses. Sanger sequencing of the DRD4 gene yielded 16 rare variants; a polygenic risk score was computed for both parents and youth. Generalized estimating equations (GEE) examined the predictive effects of parental ADHD symptoms, parental neurocognitive functioning, and poor parenting dimensions on youth ADHD as well as moderation of these effects by parental and youth DRD4 variants. Findings indicated that parental DRD4 variants moderated the impact of parental ADHD and neurocognitive functioning on youth ADHD symptoms. Youth DRD4 variants moderated the impact of parental inconsistent discipline on child ADHD. In all cases, stronger associations were observed for those individuals with more risk variants. These exploratory findings highlight the potential utility of a multiplex family design for examining the interplay between parent and child characteristics in predicting youth outcomes.