Mapping potential pathways from polygenic liability through brain structure to psychological problems across the transition to adolescence.

BACKGROUND: We used a polygenic score for externalizing behavior (extPGS) and structural MRI to examine potential pathways from genetic liability to conduct problems via the brain across the adolescent transition. METHODS: Three annual assessments of child conduct problems, attention-deficit/hyperactivity problems, and internalizing problems were conducted across across 9-13 years of age among 4,475 children of European ancestry in the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®). RESULTS: The extPGS predicted conduct problems in each wave (R2 = 2.0%-2.9%). Bifactor models revealed that the extPRS predicted variance specific to conduct problems (R2 = 1.7%-2.1%), but also variance that conduct problems shared with other measured problems (R2 = .8%-1.4%). Longitudinally, extPGS predicted levels of specific conduct problems (R2 = 2.0%), but not their slope of change across age. The extPGS was associated with total gray matter volume (TGMV; R2 = .4%) and lower TGMV predicted both specific conduct problems (R2 = 1.7%-2.1%) and the variance common to all problems in each wave (R2 = 1.6%-3.1%). A modest proportion of the polygenic liability specific to conduct problems in each wave was statistically mediated by TGMV. CONCLUSIONS: Across the adolescent transition, the extPGS predicted both variance specific to conduct problems and variance shared by all measured problems. The extPGS also was associated with TGMV, which robustly predicted conduct problems. Statistical mediation analyses suggested the hypothesis that polygenic variation influences individual differences in brain development that are related to the likelihood of conduct problems during the adolescent transition, justifying new research to test this causal hypothesis.

Using Dispositions to Understand Otherwise Intractable Causal Pathways to Psychological Problems During Childhood and Adolescence.

Studies of the genetic and environmental factors that make children more or less likely to develop distressing and impairing psychological problems, and studies of the psychobiological pathways through which these causal factors operate, have the goal of improving our understanding of the basic nature of psychological problems to develop better methods of prevention and treatment. For this reason, we have long had our eye on the prize of discovering the causes and psychobiological mechanisms underlying each dimension of psychological problems. There are compelling reasons, however, to seek a different and more achievable prize to understand psychological problems. Dimensions of psychological problems are both far too heterogeneous and too highly correlated to line up with distinct causal pathways. In contrast, a small number of orthogonal cognitive and socioemotional dispositional dimensions are correlated with psychological problems in revealing cross-cutting patterns. Each of these dispositions shares its independent causal pathways with psychological problems and help us understand the complex shared and heterogeneous nature of their causal processes. I outline a strategy for understanding the causes and mechanisms of psychological problems using studies of independently measured dispositions.

Evidence and theory for lower rates of depression in larger US urban areas.

It is commonly assumed that cities are detrimental to mental health. However, the evidence remains inconsistent and at most, makes the case for differences between rural and urban environments as a whole. Here, we propose a model of depression driven by an individual's accumulated experience mediated by social networks. The connection between observed systematic variations in socioeconomic networks and built environments with city size provides a link between urbanization and mental health. Surprisingly, this model predicts lower depression rates in larger cities. We confirm this prediction for US cities using four independent datasets. These results are consistent with other behaviors associated with denser socioeconomic networks and suggest that larger cities provide a buffer against depression. This approach introduces a systematic framework for conceptualizing and modeling mental health in complex physical and social networks, producing testable predictions for environmental and social determinants of mental health also applicable to other psychopathologies.

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology.

Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R2 = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

Using Genetics to Examine a General Liability to Childhood Psychopathology.

Psychiatric disorders show phenotypic as well as genetic overlaps. There are however also marked developmental changes throughout childhood. We investigated the extent to which, for a full range of early childhood psychopathology, a general "p" factor was explained by genetic liability, as indexed by multiple different psychiatric polygenic risk scores (PRS) and whether these relationships altered with age. The sample was a UK, prospective, population-based cohort with psychopathology data at age 7 (N = 8161) and age 13 (N = 7017). PRS were generated from large published genome-wide association studies. At both ages, we found evidence for a childhood "p" factor as well as for specific factors. Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) PRS were associated with this general "p" factor at both ages but depression and autism spectrum disorder (ASD) PRS were not. We also found some evidence of associations between schizophrenia, ADHD and depression PRS with specific factors, but these were less robust and there was evidence for developmental changes.

Accounting for Confounding in Observational Studies.

The goal of this review is to enable clinical psychology researchers to more rigorously test competing hypotheses when studying risk factors in observational studies. We argue that there is a critical need for researchers to leverage recent advances in epidemiology/biostatistics related to causal inference and to use innovative approaches to address a key limitation of observational research: the need to account for confounding. We first review theoretical issues related to the study of causation, how causal diagrams can facilitate the identification and testing of competing hypotheses, and the current limitations of observational research in the field. We then describe two broad approaches that help account for confounding: analytic approaches that account for measured traits and designs that account for unmeasured factors. We provide descriptions of several such approaches and highlight their strengths and limitations, particularly as they relate to the etiology and treatment of behavioral health problems.

Sex Differences in the Genetic and Environmental Influences on Self-Reported Non-aggressive and Aggressive Conduct Disorder Symptoms in Early and Middle Adolescence.

Decades of research into the etiology of conduct disorder (CD) has yet to yield a consensus on the existence of sex differences in underlying genetic and environmental influences. This may be partly due to the failure of many previous studies to make a distinction between non-aggressive and aggressive CD symptoms or test for potential developmental changes in sex differences in the etiology of conduct problems. To address these gaps, we fit a series of univariate and bivariate biometric sex-difference models to self-reported non-aggressive and aggressive CD symptoms in a community-based sample of twins (N = 1548, ages 9-17 year), grouped into ages 9-13 and 14-17 years. Relative model fit was evaluated using the Bayesian Information Criterion (BIC), which favors parsimony, and by Chi square difference tests. The univariate sex-scalar model provided the best fit to the data for both non-aggressive and aggressive CD symptoms at ages 9-13 and 14-17 years. Thus, the same genetic and environmental factors influenced CD symptoms in both sexes, but the total variability was lower in females than males. At both ages, the heritability of non-aggressive CD symptoms was lower than heritability of aggressive CD symptoms, and shared environmental effects were only observed for non-aggressive CD symptoms. However, estimates for genetic and environmental factors could be not be constrained to be equal across age groups for either CD subtype, suggesting substantive developmental changes in the relative influence of genetic and environmental factors on individual differences in CD symptoms. For both subtypes, the heritability was larger, and shared environmental effect smaller, in the older age group than the younger age group. A bivariate quantitative sex differences model provided the best fit to the data at ages 9-13 years. Covariation between non-aggressive and aggressive CD symptoms was due to overlapping shared and non-shared environmental factors in males and females but the overall covariation was greater in males than females. In contrast, at ages 14-17 years, the sex-scalar bivariate model provided the best fit to the data, and covariation between non-aggressive and aggressive CD symptoms was due to overlapping genetic and non-shared environmental factors. Thus, the etiology of self-reported conduct disorder varied substantially by symptom type and age. However, quantitative sex differences were only apparent when the covariation between the two subtypes was considered.

Prospective test of the developmental propensity model of antisocial behavior: from childhood and adolescence into early adulthood.

BACKGROUND: The developmental propensity model of antisocial behavior posits that several dispositional characteristics of children transact with the environment to influence the likelihood of learning antisocial behavior across development. Specifically, greater dispositional negative emotionality, greater daring, and lower prosociality-operationally, the inverse of callousness- and lower cognitive abilities are each predicted to increase risk for developing antisocial behavior. METHODS: Prospective tests of key predictions derived from the model were conducted in a high-risk sample of 499 twins who were assessed on dispositions at 10-17 years of age and assessed for antisocial personality disorder (APD) symptoms at 22-31 years of age. Predictions were tested separately for parent and youth informants on the dispositions using multiple regressions that adjusted for oversampling, nonresponse, and clustering within twin pairs, controlling demographic factors and time since the first assessment. RESULTS: Consistent with predictions, greater numbers of APD symptoms in adulthood were independently predicted over a 10-15 year span by higher youth ratings on negative emotionality and daring and lower youth ratings on prosociality, and by parent ratings of greater negative emotionality and lower prosociality. A measure of working memory did not predict APD symptoms. CONCLUSIONS: These findings support future research on the role of these dispositions in the development of antisocial behavior.

Convergent individual differences in visual cortices, but not the amygdala across standard amygdalar fMRI probe tasks.

The amygdala (AMG) has been repeatedly implicated in the processing of threatening and negatively valenced stimuli and multiple fMRI paradigms have reported personality, genetic, and psychopathological associations with individual differences in AMG activation in these paradigms. Yet the interchangeability of activations in these probes has not been established, thus it remains unclear if we can interpret AMG responses on specific tasks as general markers of its reactivity. In this study we aimed to assess if different tasks that have been widely used within the Affective Neuroscience literature consistently recruit the AMG. METHOD: Thirty-two young healthy subjects completed four fMRI tasks that have all been previously shown to probe the AMG during processing of threatening stimuli: the Threat Face Matching (TFM), the Cued Aversive Picture (CAP), the Aversive and Erotica Pictures (AEP) and the Screaming Lady paradigm (SLp) tasks. Contrasts testing response to aversive stimuli relative to baseline or neutral stimuli were generated and correlations between activations in the AMG were calculated across tasks were performed for ROIs of the AMG. RESULTS: The TFM, CAP and AEP, but not the SLp, successfully recruit the AMG, among other brain regions, especially when contrasts were against baseline or nonsocial stimuli. Conjunction analysis across contrasts showed that visual cortices (VisCtx) were also consistently recruited. Correlation analysis between the extracted data for right and left AMG did not yield significant associations across tasks. By contrast, the extracted signal in VisCtx showed significant associations across tasks (range r=0.511-r=0.630). CONCLUSIONS: Three of the four paradigms revealed significant AMG reactivity, but individual differences in the magnitudes of AMG reactivity were not correlated across paradigms. By contrast, VisCtx activation appears to be a better candidate than the AMG as a measure of individual differences with convergent validity across negative emotion processing paradigms.

Genetic and Environmental Contributions to Associations between Infant Fussy Temperament and Antisocial Behavior in Childhood and Adolescence.

Previous research suggests that fussy temperament in infancy predicts risk for later antisocial behavior (ASB) in childhood and adolescence. It remains unclear, however, to what extent infant fussiness is related to later ASB through causal processes or if they both reflect the same family risk factors for ASB. The current study used two approaches, the comparison of siblings and bivariate biometric modeling, to reduce familial confounding and examine genetic and environmental influences on associations between fussiness in the first 2 years of life and ASB in childhood and late adolescence. Analyses were conducted on data from a prospective cohort (9237 at 4-9 years and 7034 at 14-17 years) who are the offspring of a nationally representative sample of US women. In the full sample, fussiness predicted both child and adolescent ASB to small but significant extents, controlling for a wide range of measured child and family-level covariates. When siblings who differed in their fussiness were compared, fussiness predicted ASB in childhood, but not ASB during adolescence. Furthermore, results from a bivariate Cholesky model suggested that even the association of fussiness with childhood ASB found when comparing siblings is attributable to familial factors. That is, although families with infants who are higher in fussiness also tend to have children and adolescents who engage in greater ASB, the hypothesis that infant fussiness has an environmentally mediated impact on the development of future ASB was not strongly supported.

A Genetically Informed Study of the Associations Between Maternal Age at Childbearing and Adverse Perinatal Outcomes.

We examined associations of maternal age at childbearing (MAC) with gestational age and fetal growth (i.e., birth weight adjusting for gestational age), using two genetically informed designs (cousin and sibling comparisons) and data from two cohorts, a population-based Swedish sample and a nationally representative United States sample. We also conducted sensitivity analyses to test limitations of the designs. The findings were consistent across samples and suggested that, associations observed in the population between younger MAC and shorter gestational age were confounded by shared familial factors; however, associations of advanced MAC with shorter gestational age remained robust after accounting for shared familial factors. In contrast to the gestational age findings, neither early nor advanced MAC was associated with lower fetal growth after accounting for shared familial factors. Given certain assumptions, these findings provide support for a causal association between advanced MAC and shorter gestational age. The results also suggest that there are not causal associations between early MAC and shorter gestational age, between early MAC and lower fetal growth, and between advanced MAC and lower fetal growth.

Behavior problems and timing of menarche: a developmental longitudinal biometrical analysis using the NLSY-Children data.

A powerful longitudinal data source, the National Longitudinal Survey of Youth Children data, allows measurement of behavior problems (BP) within a developmental perspective linking them to menarcheal timing (MT). In a preliminary analysis, we evaluate the bivariate relationships between BP measured at different developmental periods and the timing of menarche. Correlations were not consistent with any correlational/causal relationship between BP and MT. In the major part of our study, MT was used to moderate the developmental trajectory of BP, within a genetically-informed design. Girls reaching menarche early had behavior problem variance accounted for by the shared environment; those reaching menarche with average/late timing had behavior problem differences accounted for by genetic variance. Our findings match previous empirical results in important ways, and also extend those results. A theoretical interpretation is offered in relation to a theory linking genetic/shared environmental variance to flexibility and choices available within the family in relation to BP.

Criterion validity of the general factor of psychopathology in a prospective study of girls.

BACKGROUND: The best-fitting model of the structure of common psychopathology often includes a general factor on which all dimensions of psychopathology load. Such a general factor would be important if it reflects etiologies and mechanisms shared by all dimensions of psychopathology. Nonetheless, a viable alternative explanation is that the general factor is partly or wholly a result of common method variance or other systematic measurement biases. METHODS: To test this alternative explanation, we extracted general, externalizing, and internalizing factor scores using mother-reported symptoms across 5-11 years of age in confirmatory factor analyses of data from a representative longitudinal study of 2,450 girls. Independent associations between the three psychopathology factor scores and teacher-reported criterion variables were estimated in multiple regression, controlling intelligence, and demographic covariates. RESULTS: The model including the general factor fit significantly better than a correlated two-factor (internalizing/externalizing) model. The general factor was robustly and independently associated with all measures of teacher-reported school functioning concurrently during childhood and prospectively during adolescence. CONCLUSIONS: These findings weaken the hypothesis that the general factor of psychopathology in childhood is solely a measurement artifact and support further research on the substantive meaning of the general factor.

Genetics in child and adolescent psychiatry: methodological advances and conceptual issues.

Discovering the genetic basis of early-onset psychiatric disorders has been the aim of intensive research during the last decade. We will first selectively summarize results of genetic research in child and adolescent psychiatry by using examples from different disorders and discuss methodological issues, emerging questions and future directions. In the second part of this review, we will focus on how to link genetic causes of disorders with physiological pathways, discuss the impact of genetic findings on diagnostic systems, prevention and therapeutic interventions. Finally we will highlight some ethical aspects connected to genetic research in child and adolescent psychiatry. Advances in molecular genetic methods have led to insights into the genetic architecture of psychiatric disorders, but not yet provided definite pathways to pathophysiology. If replicated, promising findings from genetic studies might in some cases lead to personalized treatments. On the one hand, knowledge of the genetic basis of disorders may influence diagnostic categories. On the other hand, models also suggest studying the genetic architecture of psychiatric disorders across diagnoses and clinical groups.

Marked reduction in serotonergic activity in a sexually aggressive adolescent male.

Serotonergic dysfunctions are implicated in conduct disorder, impulsivity, and aggression. Early adverse experiences increase the risk for these behaviors in adolescents. The authors investigated serotonergic activity in one adolescent male who experienced maternal abandonment and childhood abuse and exhibited severely aggressive sexual offenses. Platelet serotonin (5-HT) concentration, [14C]-5HT uptake kinetics, and plasma prolactin, cortisol response to D,L-fenfluramine (D,L-FEN) were measured. Results showed extremely low 5-HT concentration (2.9+/-0.7 ng/108 platelets), [14C]-5HT uptake rate (0.5+/-0.04 mM/min/107 platelets), undetectable Km and Vmax, and abnormally blunted prolactin, cortisol response to D,L-FEN. These abnormalities in this sexually aggressive adolescent may be a consequence of childhood abuse.

Impulsivity and the modular organization of resting-state neural networks.

Impulsivity is a complex trait associated with a range of maladaptive behaviors, including many forms of psychopathology. Previous research has implicated multiple neural circuits and neurotransmitter systems in impulsive behavior, but the relationship between impulsivity and organization of whole-brain networks has not yet been explored. Using graph theory analyses, we characterized the relationship between impulsivity and the functional segregation ("modularity") of the whole-brain network architecture derived from resting-state functional magnetic resonance imaging (fMRI) data. These analyses revealed remarkable differences in network organization across the impulsivity spectrum. Specifically, in highly impulsive individuals, regulatory structures including medial and lateral regions of the prefrontal cortex were isolated from subcortical structures associated with appetitive drive, whereas these brain areas clustered together within the same module in less impulsive individuals. Further exploration of the modular organization of whole-brain networks revealed novel shifts in the functional connectivity between visual, sensorimotor, cortical, and subcortical structures across the impulsivity spectrum. The current findings highlight the utility of graph theory analyses of resting-state fMRI data in furthering our understanding of the neurobiological architecture of complex behaviors.

Operating characteristics of alternative statistical methods for detecting gene-by-measured environment interaction in the presence of gene-environment correlation in twin and sibling studies.

It is likely that all complex behaviors and diseases result from interactions between genetic vulnerabilities and environmental factors. Accurately identifying such gene-environment interactions is of critical importance for genetic research on health and behavior. In a previous article we proposed a set of models for testing alternative relationships between a phenotype (P) and a putative moderator (M) in twin studies. These include the traditional bivariate Cholesky model, an extension of that model that allows for interactions between M and the underling influences on P, and a model in which M has a non-linear main effect on P. Here we use simulations to evaluate the type I error rates, power, and performance of the Bayesian Information Criterion under a variety of data generating mechanisms and samples sizes (n = 2,000 and n = 500 twin pairs). In testing the extension of the Cholesky model, false positive rates consistently fell short of the nominal Type I error rates ([Formula: see text]). With adequate sample size (n = 2,000 pairs), the correct model had the lowest BIC value in nearly all simulated datasets. With lower sample sizes, models specifying non-linear main effects were more difficult to distinguish from models containing interaction effects. In addition, we provide an illustration of our approach by examining possible interactions between birthweight and the genetic and environmental influences on child and adolescent anxiety using previously collected data. We found a significant interaction between birthweight and the genetic and environmental influences on anxiety. However, the interaction was accounted for by non-linear main effects of birthweight on anxiety, verifying that interaction effects need to be tested against alternative models.

Early concern and disregard for others as predictors of antisocial behavior.

BACKGROUND: Prediction of antisocial behavior is important, given its adverse impact on both the individuals engaging in antisocial behavior and society. Additional research identifying early predictors of future antisocial behavior, or antisocial propensity, is needed. The present study tested the hypothesis that both concern for others and active disregard for others in distress in toddlers and young children predict antisocial behavior during middle childhood and adolescence. METHODS: A representative sample of same-sex twins (N=956) recruited in Colorado was examined. Mother-rated and researcher-observed concern and disregard for others assessed at age 14-36 months were examined as predictors of parent- (age 4-12), teacher- (age 7-12), and self-reported (age 17) antisocial behavior. RESULTS: Observed disregard for others predicted antisocial behavior assessed by three different informants (parents, teachers, and self), including antisocial behavior assessed 14 years later. It also predicted a higher order antisocial behavior factor (ß=.58, p<.01) after controlling for observed concern for others. Mother-rated disregard for others predicted parent-reported antisocial behavior. Contrary to predictions, neither mother-rated nor observed concern for others inversely predicted antisocial behavior. RESULTS of twin analyses suggested that the covariation between observed disregard for others and antisocial behavior was due to shared environmental influences. CONCLUSIONS: Disregard for others in toddlerhood/early childhood is a strong predictor of antisocial behavior in middle childhood and adolescence. The results suggest the potential need for early assessment of disregard for others and the development of potential interventions.

Critical need for family-based, quasi-experimental designs in integrating genetic and social science research.

Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles.