Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies.

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.

Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies.

Marginal effect estimates in genome-wide association studies (GWAS) are mixtures of direct and indirect genetic effects. Existing methods to dissect these effects require family-based, individual-level genetic, and phenotypic data with large samples, which is difficult to obtain in practice. Here, we propose a statistical framework to estimate direct and indirect genetic effects using summary statistics from GWAS conducted on own and offspring phenotypes. Applied to birth weight, our method showed nearly identical results with those obtained using individual-level data. We also decomposed direct and indirect genetic effects of educational attainment (EA), which showed distinct patterns of genetic correlations with 45 complex traits. The known genetic correlations between EA and higher height, lower body mass index, less-active smoking behavior, and better health outcomes were mostly explained by the indirect genetic component of EA. In contrast, the consistently identified genetic correlation of autism spectrum disorder (ASD) with higher EA resides in the direct genetic component. A polygenic transmission disequilibrium test showed a significant overtransmission of the direct component of EA from healthy parents to ASD probands. Taken together, we demonstrate that traditional GWAS approaches, in conjunction with offspring phenotypic data collection in existing cohorts, could greatly benefit studies on genetic nurture and shed important light on the interpretation of genetic associations for human complex traits.

A prospective longitudinal study of multidomain resilience among youths with and without maltreatment histories.

The majority of children with maltreatment histories do not go on to develop depression in their adolescent and adult years. These individuals are often identified as being "resilient", but this characterization may conceal difficulties that individuals with maltreatment histories might face in their interpersonal relationships, substance use, physical health, and/or socioeconomic outcomes in their later lives. This study examined how adolescents with maltreatment histories who exhibit low levels of depression function in other domains during their adult years. Longitudinal trajectories of depression (across ages 13-32) in individuals with (n = 3,809) and without (n = 8,249) maltreatment histories were modeled in the National Longitudinal Study of Adolescent to Adult Health. The same "Low," "increasing," and "declining" depression trajectories in both individuals with and without maltreatment histories were identified. Youths with maltreatment histories in the "low" depression trajectory reported lower romantic relationship satisfaction, more exposure to intimate partner and sexual violence, more alcohol abuse/dependency, and poorer general physical health compared to individuals without maltreatment histories in the same "low" depression trajectory in adulthood. Findings add further caution against labeling individuals as "resilient" based on a just single domain of functioning (low depression), as childhood maltreatment has harmful effects on a broad spectrum of functional domains.

Childhood exposure to interpersonal violence is associated with greater transdiagnostic integration of psychiatric symptoms.

BACKGROUND: Childhood exposure to interpersonal violence (IPV) may be linked to distinct manifestations of mental illness, yet the nature of this change remains poorly understood. Network analysis can provide unique insights by contrasting the interrelatedness of symptoms underlying psychopathology across exposed and non-exposed youth, with potential clinical implications for a treatment-resistant population. We anticipated marked differences in symptom associations among IPV-exposed youth, particularly in terms of 'hub' symptoms holding outsized influence over the network, as well as formation and influence of communities of highly interconnected symptoms. METHODS: Participants from a population-representative sample of youth (n = 4433; ages 11-18 years) completed a comprehensive structured clinical interview assessing mental health symptoms, diagnostic status, and history of violence exposure. Network analytic methods were used to model the pattern of associations between symptoms, quantify differences across diagnosed youth with (IPV+) and without (IPV-) IPV exposure, and identify transdiagnostic 'bridge' symptoms linking multiple disorders. RESULTS: Symptoms organized into six 'disorder' communities (e.g. Intrusive Thoughts/Sensations, Depression, Anxiety), that exhibited considerably greater interconnectivity in IPV+ youth. Five symptoms emerged in IPV+ youth as highly trafficked 'bridges' between symptom communities (11 in IPV- youth). CONCLUSION: IPV exposure may alter mutually reinforcing symptom co-occurrence in youth, thus contributing to greater psychiatric comorbidity and treatment resistance. The presence of a condensed and unique set of bridge symptoms suggests trauma-enriched nodes which could be therapeutically targeted to improve outcomes in violence-exposed youth.

The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

Genome-wide association study reveals sex-specific genetic architecture of facial attractiveness.

Facial attractiveness is a complex human trait of great interest in both academia and industry. Literature on sociological and phenotypic factors associated with facial attractiveness is rich, but its genetic basis is poorly understood. In this paper, we conducted a genome-wide association study to discover genetic variants associated with facial attractiveness using 4,383 samples in the Wisconsin Longitudinal Study. We identified two genome-wide significant loci, highlighted a handful of candidate genes, and demonstrated enrichment for heritability in human tissues involved in reproduction and hormone synthesis. Additionally, facial attractiveness showed strong and negative genetic correlations with BMI in females and with blood lipids in males. Our analysis also suggested sex-specific selection pressure on variants associated with lower male attractiveness. These results revealed sex-specific genetic architecture of facial attractiveness and provided fundamental new insights into its genetic basis.

The positive end of the polygenic score distribution for ADHD: a low risk or a protective factor?

BACKGROUND: Polygenic scores (PGS) are widely used to characterize genetic liability for heritable mental disorders, including attention-deficit/hyperactivity disorder (ADHD). However, little is known about the effects of a low burden of genetic liability for ADHD, including whether this functions as a low risk or protective factor for ADHD and related functional outcomes in later life. The current study examines the association of low ADHD PGS and functional outcomes in adulthood. METHODS: Participants were from Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health) (N = 7088; mean age = 29, s.d. = 1.74). ADHD PGS was computed from an existing genome-wide association study, and adult functional outcomes, including cognition, educational attainment, mental health, and physical health were assessed during in-home interviews. RESULTS: Individuals at the lowest end of the ADHD PGS distribution (i.e. lowest 20th percentile) had the lowest probabilities of ADHD, exhibiting a 17-19% reduction in risk for ADHD relative to the observed 8.3% prevalence rate of ADHD in Add Health. Furthermore, individuals with low ADHD PGS had higher cognitive performance, greater levels of educational attainment, and lower BMI relative to individuals representing the rest of the ADHD PGS distribution, including those who were in the medium and high-PGS groups. CONCLUSIONS: Findings indicate that psychiatric PGS likely capture far more than just the risk and the absence of risk for a psychiatric outcome; where one lies along the PGS distribution may predict diverging functional consequences, for better and for worse.

Factorial invariance in hierarchical factor models of mental disorders in African American and European American youths.

BACKGROUND: There is converging evidence that mental disorders are more optimally conceptualized in a hierarchical framework (i.e., the Hierarchical Taxonomy of Psychopathology, HiTOP) that transcends the categorical boundaries of the Diagnostic and Statistical Manual of Mental Disorders (DSM). However, the majority of this evidence comes from studies that draw upon predominantly European American or Caucasian populations. Whether a hierarchical conceptualization of mental disorders generalizes across racial-ethnic groups, including for African American (AA) populations, is unclear. METHODS: We tested multidimensional and bifactor models of 15 DSM diagnoses and psychiatric traits in two groups, including AA (n = 3,088) and European American (EA; n = 5,147) youths aged 8-21 from the Philadelphia Neurodevelopmental Cohort (PNC). We also conducted multigroup confirmatory factor analyses to test for factorial invariance between the best fitting AA and EA multidimensional and bifactor models. RESULTS: In the multidimensional model tests, a three-factor model, specifying internalizing, externalizing, and thought dimensions, emerged as the best fitting model for AAs and EAs. In the bifactor model tests, a three-factor model (i.e., internalizing, externalizing, and thought dimensions) that also specified a general factor emerged as the optimal for both AAs and EAs. The general factor accounted for a significant proportion of the covariation between the secondary factors and the individual disorders and traits. Furthermore, both models were factorially invariant, indicating no significant difference in the factor structure of mental disorders between AAs and EAs in PNC. CONCLUSIONS: Results suggest that the hierarchical factor structure of mental disorders may be racial-ethnically robust. This finding has implications for etiological and epidemiological studies focused on racial-ethnic subgroup comparisons, particularly with respect to identifying similarities and differences in prevalence rates or sociodemographic risk factors for mental disorders.

Assessing phenotypic and polygenic models of ADHD to identify mechanisms of risk for longitudinal trajectories of externalizing behaviors.

BACKGROUND: Children with ADHD frequently engage in higher rates of externalizing behaviors in adulthood relative to children without. However, externalizing behaviors vary across development. Little is known about how this risk unfolds across development. Phenotypic and polygenic models of childhood ADHD were used to predict individual differences in adult externalizing trajectories. Supportive parenting, school connectedness, and peer closeness were then examined as causal mechanisms. METHODS: Data were from the National Longitudinal Study of Adolescent to Adult Health (N = 7,674). Externalizing behavior was measured using data from age 18 to 32 and modeled using latent class growth analysis. Child ADHD was measured using retrospective self-report (phenotypic model) and genome-wide polygenic risk scores (polygenic model). Multiple mediation models examined the direct and indirect effects of the phenotypic and polygenic models (separately) on externalizing trajectories through the effects of adolescent supportive parenting, school connectedness, and peer closeness. RESULTS: Phenotypic and polygenic models of ADHD were associated with being in the High Decreasing (3.2% of sample) and Moderate (16.1%) adult externalizing trajectories, but not the severe Low Increasing trajectory (2.6%), relative to the Normal trajectory (78.2%). Associations between both models of ADHD on the High Decreasing and Moderate trajectories were partially mediated through the effects of school connectedness, but not supportive parenting or peer closeness. CONCLUSIONS: Findings shed light on how childhood ADHD affects downstream psychosocial processes that then predict specific externalizing outcomes in adulthood. They also reinforce the importance of fostering a strong school environment for adolescents with (and without) ADHD, as this context plays a critical role in shaping the development of externalizing behaviors in adulthood.

The influence of parents and schools on developmental trajectories of antisocial behaviors in Caucasian and African American youths.

African American youths are overrepresented in the American juvenile justice system relative to Caucasians. Yet, research on antisocial behaviors (ASB) has focused on predominantly Caucasian populations. Furthermore, relatively little is known about how environmental factors, such as supportive parenting (e.g., how close adolescents feel to their parent) and school connectedness (e.g., how supported adolescents feel at school), affect trajectories of ASB in Caucasians versus African Americans. This study mapped developmental trajectories of ASB in Caucasians (n = 10,764) and African Americans (n = 4,091) separately, using four waves of data from the National Longitudinal Study of Adolescent to Adult Health. We then examined supportive parenting and school connectedness on the trajectories of ASB. Four trajectories of ASB were identified for both Caucasians and African Americans: negligible, adolescence-peaked, low-persistence, and high-persistence ASB, although prevalence rates differed by racial-ethnic status. Supportive parenting reduced the risk of membership into the adolescence-peaked trajectory for both Caucasians and African Americans. However, school connectedness was less protective for African Americans than for Caucasians because it only predicted a lower risk of adolescence-peaked membership for African Americans. Findings may reflect the complex social dynamics between race and schools in the development of ASB.

The Impact of Peer Substance Use and Polygenic Risk on Trajectories of Heavy Episodic Drinking Across Adolescence and Emerging Adulthood.

BACKGROUND: Heavy episodic drinking is developmentally normative among adolescents and young adults, but is linked to adverse consequences in later life, such as drug and alcohol dependence. Genetic and peer influences are robust predictors of heavy episodic drinking in youth, but little is known about the interplay between polygenic risk and peer influences as they impact developmental patterns of heavy episodic drinking. METHODS: Data were from a multisite prospective study of alcohol use among adolescents and young adults with genome-wide association data (n = 412). Generalized linear mixed models were used to characterize the initial status and slopes of heavy episodic drinking between age 15 and 28. Polygenic risk scores (PRS) were derived from a separate genome-wide association study for alcohol dependence and examined for their interaction with substance use among the adolescents' closest friends in predicting the initial status and slopes of heavy episodic drinking. RESULTS: Close friend substance use was a robust predictor of adolescent heavy episodic drinking, even after controlling for parental knowledge and peer substance use in the school. PRS were predictive of the initial status and early patterns of heavy episodic drinking in males, but not in females. No interaction was detected between PRS and close friend substance use for heavy episodic drinking trajectories in either males or females. CONCLUSIONS: Although substance use among close friends and genetic influences play an important role in predicting heavy episodic drinking trajectories, particularly during the late adolescent to early adult years, we found no evidence of interaction between these influences after controlling for other social processes, such as parental knowledge and broader substance use among other peers outside of close friends. The use of longitudinal models and accounting for multiple social influences may be crucial for future studies focused on uncovering gene-environment interplay. Clinical implications are also discussed.

Assessing the interplay between multigenic and environmental influences on adolescent to adult pathways of antisocial behaviors.

The current investigation utilized a developmental psychopathology approach to test the hypothesis that multigenic (i.e., dopaminergic and serotonergic genes) and multienvironmental factors interactively contribute to developmental pathways of antisocial behavior (ASB). A sample of 8,834 Caucasian individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health) were used to (a) examine the developmental pathways of ASB from age 13 to 32 using growth mixture modeling, (b) compute weighted multigenic risk scores (Add Health MRS) for ASB from six well-characterized polymorphisms in dopamine and serotonin genes, and (c) test the interaction between the Add Health MRS and a measures of support (incorporating indicators of both positive and negative support from parents and schools). Four pathways of adolescent to adult ASB emerged from the growth mixture models: low, adolescence-peaked, high decline, and persistent. Add Health MRS predicted the persistent ASB pathway, but not other ASB pathways. Males with high Add Health MRS, but not low MRS, had significantly greater odds of being in the adolescence-peaked pathway relative to the low pathway at low levels of school connectedness. Nonfamilial environmental influences during adolescence may have a cumulative impact on the development of ASB, particularly among males with greater underlying genetic risks.

A Hierarchical Factor Model of Executive Functions in Adolescents: Evidence of Gene-Environment Interplay.

Executive functions (EF) are a complex set of neurodevelopmental, higher-ordered processes that are especially salient during adolescence. Disruptions to these processes are predictive of psychiatric problems in later adolescence and adulthood. The objectives of the current study were to characterize the latent structure of EF using bifactor analysis and to investigate the independent and interactive effects of genes and environments on EF during adolescence. Using a representative young adolescent sample, we tested the interaction of a polymorphism in the serotonin transporter gene (5-HTTLPR) and parental supervision for EF through hierarchical linear regression. To account for the possibility of a hierarchical factor structure for EF, a bifactor analysis was conducted on the eight subtests of the Delis-Kaplan Executive Functions System (D-KEFS). The bifactor analysis revealed the presence of a general EF construct and three EF subdomains (i.e., conceptual flexibility, inhibition, and fluency). A significant 5-HTTLPR by parental supervision interaction was found for conceptual flexibility, but not for general EF, fluency or inhibition. Specifically, youth with the L/L genotype had significantly lower conceptual flexibility scores compared to youth with S/S or S/L genotypes given low levels of parental supervision. Our findings indicate that adolescents with the L/L genotype were especially vulnerable to poor parental supervision on EF. This vulnerability may be amenable to preventive interventions.

Parenting Behavior Mediates the Intergenerational Association of Parent and Child Offspring ADHD Symptoms.

Although there are likely to be multiple mechanisms underlying parent attention-deficit/hyperactivity disorder (ADHD) symptoms as a key risk factor for offspring ADHD, potential explanatory factors have yet to be reliably identified. Given that parent ADHD symptoms independently predict parenting behavior and child ADHD symptoms, we tested whether individual differences in multiple dimensions of positive and negative parenting behavior (i.e., corporal punishment, inconsistent discipline, positive parenting behavior, observed negative talk, and observed praise) mediated the association between parental and offspring ADHD. We used a prospective design that featured predictors (i.e., parent ADHD symptoms) and mediators (i.e., parenting behavior) that temporally preceded the outcome (i.e., offspring ADHD symptoms). Using a well-characterized sample of 120 children with and without ADHD (ages 5-10 at Wave 1, 7-12 at Wave 2) and their biological parents, we examined multimethod (i.e., observed, self-report) measures of positive and negative parenting behavior as simultaneous mediators of the association of Wave 1 parent and Wave 2 offspring ADHD symptoms. Using a multiple mediation framework, consisting of rigorous bootstrapping procedures and controlling for parent depression, child's baseline ADHD and oppositional defiant disorder, and child's age, corporal punishment significantly and uniquely mediated the association of Wave 1 parent ADHD symptoms and Wave 2 offspring ADHD. We consider the role of parenting behavior in the intergenerational transmission of ADHD as well as implications of these findings for the intervention and prevention of childhood ADHD.

Microstructural neural correlates of maximal grip strength in autistic children: the role of the cortico-cerebellar network and attention-deficit/hyperactivity disorder features.

Introduction: Maximal grip strength, a measure of how much force a person's hand can generate when squeezing an object, may be an effective method for understanding potential neurobiological differences during motor tasks. Grip strength in autistic individuals may be of particular interest due to its unique developmental trajectory. While autism-specific differences in grip-brain relationships have been found in adult populations, it is possible that such differences in grip-brain relationships may be present at earlier ages when grip strength is behaviorally similar in autistic and non-autistic groups. Further, such neural differences may lead to the later emergence of diagnostic-group grip differences in adolescence. The present study sought to examine this possibility, while also examining if grip strength could elucidate the neuro-motor sources of phenotypic heterogeneity commonly observed within autism. Methods: Using high resolution, multi-shell diffusion, and quantitative R1 relaxometry imaging, this study examined how variations in key sensorimotor-related white matter pathways of the proprioception input, lateral grasping, cortico-cerebellar, and corticospinal networks were associated with individual variations in grip strength in 68 autistic children and 70 non-autistic (neurotypical) children (6-11 years-old). Results: In both groups, results indicated that stronger grip strength was associated with higher proprioceptive input, lateral grasping, and corticospinal (but not cortico-cerebellar modification) fractional anisotropy and R1, indirect measures concordant with stronger microstructural coherence and increased myelination. Diagnostic group differences in these grip-brain relationships were not observed, but the autistic group exhibited more variability particularly in the cortico-cerebellar modification indices. An examination into the variability within the autistic group revealed that attention-deficit/hyperactivity disorder (ADHD) features moderated the relationships between grip strength and both fractional anisotropy and R1 relaxometry in the premotor-primary motor tract of the lateral grasping network and the cortico-cerebellar network tracts. Specifically, in autistic children with elevated ADHD features (60% of the autistic group) stronger grip strength was related to higher fractional anisotropy and R1 of the cerebellar modification network (stronger microstructural coherence and more myelin), whereas the opposite relationship was observed in autistic children with reduced ADHD features. Discussion: Together, this work suggests that while the foundational elements of grip strength are similar across school-aged autistic and non-autistic children, neural mechanisms of grip strength within autistic children may additionally depend on the presence of ADHD features. Specifically, stronger, more coherent connections of the cerebellar modification network, which is thought to play a role in refining and optimizing motor commands, may lead to stronger grip in children with more ADHD features, weaker grip in children with fewer ADHD features, and no difference in grip in non-autistic children. While future research is needed to understand if these findings extend to other motor tasks beyond grip strength, these results have implications for understanding the biological basis of neuromotor control in autistic children and emphasize the importance of assessing co-occurring conditions when evaluating brain-behavior relationships in autism.

Sensorimotor Features and Daily Living Skills in Autistic Children With and Without ADHD.

Attention-deficit/hyperactivity disorder (ADHD) commonly co-occurs in autistic children. However, additional research is needed to explore the differences in motor skills and sensory features in autistic children with and without ADHD, as well as the impacts of these factors on daily living skills (DLS). This observational study sought to fill this gap with 67 autistic children (6.14-10.84 years-old), 43 of whom had ADHD. Autistic children with ADHD demonstrated higher sensory features and lower motor skills than autistic children without ADHD. In examining autism and ADHD features dimensionally, we found that overall sensory features, seeking, and hyporesponsiveness were driven by both autism and ADHD features, whereas motor skills, enhanced perception, and hyperresponsiveness were driven by only autism features. Additionally, in using these dimensional variables of autism and ADHD features, we found that differences in motor skills, sensory and autism features, but not ADHD features, impact DLS of autistic children, with autism features and motor skills being the strongest individual predictors of DLS. Together, these results demonstrate the uniqueness of motor skills and sensory features in autistic children with and without ADHD, as well as how autism features, sensory features, and motor skills contribute to DLS, emphasizing the importance of a comprehensive understanding of each individual and complexities of human development when supporting autistic children.

Differential susceptibility in longitudinal models of gene-environment interaction for adolescent depression.

Although family support reliably predicts the development of adolescent depression and suicidal behaviors, relatively little is known about the interplay of family support with potential genetic factors. We tested the association of the 44 base pair polymorphism in the serotonin transporter linked promoter region gene (5-HTTLPR), family support (i.e., cohesion, communication, and warmth), and their interaction with self-reported depression symptoms and risk for suicide in 1,030 Caucasian adolescents and young adults from the National Longitudinal Study of Adolescent Health. High-quality family support predicted fewer symptoms of depression and reduced risk for suicidality. There was also a significant interaction between 5-HTTLPR and family support for boys and a marginally significant interaction for girls. Among boys with poor family support, youth with at least one short allele had more symptoms of depression and a higher risk for suicide attempts relative to boys homozygous for the long allele. However, in the presence of high family support, boys with the short allele had the fewest depression symptoms (but not suicide attempts). Results suggest that the short allele may increase reactivity to both negative and positive family influences in the development of depression. We discuss the potential role of interactive exchanges between family support and offspring genotype in the development of adolescent depression and suicidal behaviors.

Interaction of dopamine transporter gene and observed parenting behaviors on attention-deficit/hyperactivity disorder: a structural equation modeling approach.

Emerging evidence suggests that some individuals may be simultaneously more responsive to the effects from environmental adversity and enrichment (i.e., differential susceptibility). Given that parenting behavior and a variable number tandem repeat polymorphism in the 3'untranslated region of the dopamine transporter (DAT1) gene are each independently associated with attention-deficit/hyperactivity disorder (ADHD), our goal was to evaluate the potential interactive effects of child DAT1 genotype with positive and negative parenting behaviors on childhood ADHD. We recruited an ethnically diverse sample of 150 six- to nine-year-old boys and girls with and without ADHD. Children were genotyped for a common polymorphism of the DAT1 gene, and objective counts of observed parenting behavior (i.e., negativity and praise) were obtained from a valid parent-child interaction task. Structural equation modeling was used to examine the interactive effects of DAT1 and observed parenting with a latent ADHD factor. We detected a significant interaction between observed praise and child DAT1 (coded additively), which suggested that praise was associated with increased ADHD, but only among youth with the 9/10 genotype. In addition, a marginally significant interaction between DAT1 (coded additively and recessively) and observed negativity emerged for ADHD, such that negativity was positively associated with ADHD but only for youth with the 9/9 genotype. Although differential susceptibility theory was not fully supported, these preliminary results suggest that interactive exchanges between parenting behavior and child genotype potentially contribute to the development of ADHD. Clinical implications for interactions between parenting behavior and child genotype are discussed.

Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort.

BACKGROUND: ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. METHODS: Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. RESULTS: A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. CONCLUSIONS: The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.

Interaction of dopamine transporter (DAT1) genotype and maltreatment for ADHD: a latent class analysis.

BACKGROUND: Although the association of the dopamine transporter (DAT1) gene and attention-deficit/hyperactivity disorder (ADHD) has been widely studied, far less is known about its potential interaction with environmental risk factors. Given that maltreatment is a replicated risk factor for ADHD, we explored the interaction between DAT1 and maltreatment with ADHD symptoms defined dimensionally and using latent class analysis (LCA). METHOD: We tested the association of the 40 base-pair variable number of tandem repeats polymorphism in DAT1, maltreatment, and their interaction in 2,488 boys and girls from the National Longitudinal Study of Adolescent Health. RESULTS: In boys, ADHD symptoms were optimally defined by four classes (Combined, Hyperactive/Impulsive, Inattentive, and Normal), whereas in girls, ADHD symptoms were defined by three classes (Combined, Combined-Mild, Normal). A significant DAT1 × maltreatment interaction revealed that maltreated girls homozygous for the 10-repeat allele had more symptoms of ADHD, and were also 2.5 times more likely to be classified in the Combined ADHD group than in the Normal Group. CONCLUSIONS: The underlying structure of ADHD symptoms differed between boys and girls and DAT1 interacted with maltreatment to predict ADHD symptoms and ADHD status derived from LCA. Interactive exchanges between maltreatment and DAT1 for ADHD symptoms, and their implications for intervention, are discussed.