Trans-ancestry meta-analysis of genome wide association studies of inhibitory control.

Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries (N = 14,877) using cognitive traits derived from the stop-signal task, namely - go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.

Disentangling differing relationships between internalizing disorders and alcohol use.

Both internalizing disorders and alcohol use have dramatic, wide-spread implications for global health. Previous work has established common phenotypic comorbidity among these disorders, as well as shared genetic variation underlying them both. We used genomic structural equation modeling to investigate the shared genetics of internalizing, externalizing, and alcohol use traits, as well as to explore whether specific domains of internalizing symptoms mediate the contrasting relationships with problematic alcohol use compared to alcohol consumption. We also examined patterns of genetic correlations between similar traits within additional Finnish and East Asian ancestry groups. When the shared genetic influence of externalizing psychopathology was accounted for, the genetic effect of internalizing traits on alcohol use was reduced, suggesting the important role of common genetic factors underlying multiple psychiatric disorders and their genetic influences on comorbidity of internalizing and alcohol use traits. Individual internalizing domains had contrasting effects on frequency of alcohol consumption, which demonstrate the complex system of pleiotropy that exists, even within similar disorders, and can be missed when evaluating only relationships among formal diagnoses. Future work must consider the broad effects of shared psychopathology along with the fine-scale effects of heterogeneity within disorders to more fully understand the biology underlying complex traits.

Associations Between Adolescent Pain and Psychopathology in the Adolescent Brain Cognitive Development (ABCD) Study.

Pain and psychopathology co-occur in adolescence, but the directionality and etiology of these associations are unclear. Using the pain questionnaire and the Child Behavior Checklist from the Adolescent Brain Cognitive Development study (n = 10,414 children [770 twin pairs] aged 12-13), we estimated longitudinal, co-twin control, and twin models to evaluate the nature of these associations. In two-wave cross-lag panel models, there were small cross-lag effects that suggested bidirectional associations. However, the co-twin control models suggested that most associations were familial. Pain at age 12 and 13 was mostly environmental (A = 0-12%, C = 15-30%, E = 70-73%) and the twin models suggested that associations with psychopathology were primarily due to shared environmental correlations. The exception was externalizing, which had a phenotypic prospective effect on pain, a significant within-family component, and a non-shared environmental correlation at age 12. Environmental risk factors may play a role in pain-psychopathology co-occurrence. Future studies can examine risk factors such as stressful life events.

Heritability Estimation of Cognitive Phenotypes in the ABCD Study® Using Mixed Models.

Twin and family studies have historically aimed to partition phenotypic variance into components corresponding to additive genetic effects (A), common environment (C), and unique environment (E). Here we present the ACE Model and several extensions in the Adolescent Brain Cognitive Development℠ Study (ABCD Study®), employed using the new Fast Efficient Mixed Effects Analysis (FEMA) package. In the twin sub-sample (n = 924; 462 twin pairs), heritability estimates were similar to those reported by prior studies for height (twin heritability = 0.86) and cognition (twin heritability between 0.00 and 0.61), respectively. Incorporating SNP-derived genetic relatedness and using the full ABCD Study® sample (n = 9,742) led to narrower confidence intervals for all parameter estimates. By leveraging the sparse clustering method used by FEMA to handle genetic relatedness only for participants within families, we were able to take advantage of the diverse distribution of genetic relatedness within the ABCD Study® sample.

Anxiety trajectories among cancer survivors during the COVID-19 pandemic.

PURPOSE: To describe trajectories of general and bodily vigilance anxiety among cancer survivors during COVID-19 and examine associated factors. DESIGN: Longitudinal survey study (May-December 2020). SAMPLE: Colorado-based cancer survivors (N = 147). METHODS: Latent class growth analyses were used to examine trajectories for two types of anxiety (general and body vigilance), and to evaluate associations with fear of cancer recurrence (FCR), loneliness, and emotional approach coping. FINDINGS: Anxiety levels remained stable over time. Most participants were best characterized by the mild general anxiety and moderate bodily vigilance anxiety classes. FCR predicted both general and bodily vigilance anxiety class, and loneliness distinguished between mild and moderate bodily vigilance anxiety classes. CONCLUSIONS: Current cancer survivors experienced mild general anxiety and moderate body vigilance anxiety during the early pandemic with no detectable improvement over time, and FCR consistently predicted anxiety outcomes. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS: These findings provide insight into the anxiety profiles of cancer survivors during COVID-19 and possible therapeutic targets.

Context-specific activations are a hallmark of the neural basis of individual differences in general executive function.

Common executive functioning (cEF) is a domain-general factor that captures shared variance in performance across diverse executive function tasks. To investigate the neural mechanisms of individual differences in cEF (e.g., goal maintenance, biasing), we conducted the largest fMRI study of multiple executive tasks to date (N = 546). Group average activation during response inhibition (antisaccade task), working memory updating (keep track task), and mental set shifting (number-letter switch task) overlapped in classic cognitive control regions. However, there were no areas across tasks that were consistently correlated with individual differences in cEF ability. Although similar brain areas are recruited when completing different executive function tasks, activation levels of those areas are not consistently associated with better performance. This pattern is inconsistent with a simple model in which higher cEF is associated with greater or less activation of a set of control regions across different task contexts; however, it is potentially consistent with a model in which individual differences in cEF primarily depend on activation of domain-specific targets of executive function. Brain features that explain commonalities in executive function performance across tasks remain to be discovered.

Genetic and environmental influences on executive functions and intelligence in middle childhood.

Executive functions (EFs) and intelligence (IQ) are phenotypically correlated. In twin studies, latent variables for EFs and IQ display moderate to high heritability estimates; however, they show variable genetic correlations in twin studies spanning childhood to middle age. We analyzed data from over 11,000 children (9- to 10-year-olds, including 749 twin pairs) in the Adolescent Brain Cognitive Development (ABCD) Study to examine the phenotypic and genetic relations between EFs and IQ in childhood. We identified two EF factors-Common EF and Updating-Specific-which were both related to IQ (rs = 0.64-0.81). Common EF and IQ were heritable (53%-67%), and their genetic correlation (rG = 0.86) was not significantly different than 1. These results suggest that EFs and IQ are phenotypically but not genetically separable in middle childhood, meaning that this phenotypic separability may be influenced by environmental factors.

Heritability of brain resilience to perturbation in humans.

Resilience is the capacity of complex systems to persist in the face of external perturbations and retain their functional properties and performance. In the present study, we investigated how individual variations in brain resilience, which might influence response to stress, aging and disease, are influenced by genetics and/or the environment, with potential implications for the implementation of resilience-boosting interventions. Resilience estimates were derived from in silico lesioning of either brain regions or functional connections constituting the connectome of healthy individuals belonging to two different large and unique datasets of twins, specifically: 463 individual twins from the Human Connectome Project and 453 individual twins from the Colorado Longitudinal Twin Study. As has been reported previously, moderate heritability was found for several topological indexes of brain efficiency and modularity. Importantly, evidence of heritability was found for resilience measures based on removal of brain connections rather than specific single regions, suggesting that genetic influences on resilience are preferentially directed toward region-to-region communication rather than local brain activity. Specifically, the strongest genetic influence was observed for moderately weak, long-range connections between a specific subset of functional brain networks: the Default Mode, Visual and Sensorimotor networks. These findings may help identify a link between brain resilience and network-level alterations observed in neurological and psychiatric diseases, as well as inform future studies investigating brain shielding interventions against physiological and pathological perturbations.

Genetic and Environmental Influences on Stressful Life Events and their Associations with Executive Functions in Young Adulthood: A Longitudinal Twin Analysis.

Although stress is frequently considered an environmental factor, dependent stressful life events (SLEs)--stressors that result from one's actions or behaviors--may in fact be evoked by a genetic liability. It has been suggested that dependent SLEs may be partially caused by poor executive function (EFs), higher-level cognitive abilities that enable individuals to implement goal-directed behavior. We investigated the possibility of genetic and environmental overlap between SLEs and EFs in a longitudinal twin study. We found high genetic stability in the number of dependent SLEs from age 23 to age 29, suggesting that the number of dependent stressors show persistence across time due to their genetic etiology. In addition, there was a nominally significant negative genetic correlation between a Common EF latent factor and dependent SLEs at age 23. The genetic stability of dependent SLEs and association with Common EF provides insight into how some behaviors may lead to persistent stress.

Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry.

INTRODUCTION: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction. METHODS: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µâ€Šage = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components. RESULTS: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (ß = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited. CONCLUSIONS: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk. IMPLICATIONS: These findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences.

Genetic and Environmental Influence on the Human Functional Connectome.

Detailed mapping of genetic and environmental influences on the functional connectome is a crucial step toward developing intermediate phenotypes between genes and clinical diagnoses or cognitive abilities. We analyzed resting-state functional magnetic resonance imaging data from two adult twin samples (Nos = 446 and 371) to quantify genetic and environmental influence on all pairwise functional connections between 264 brain regions (~35 000 functional connections). Nonshared environmental influence was high across the whole connectome. Approximately 14-22% of connections had nominally significant genetic influence in each sample, 4.6% were significant in both samples, and 1-2% had heritability estimates greater than 30%. Evidence of shared environmental influence was weak. Genetic influences on connections were distinct from genetic influences on a global summary measure of the connectome, network-based estimates of connectivity, and movement during the resting-state scan, as revealed by a novel connectome-wide bivariate genetic modeling procedure. The brain's genetic organization is diverse and not as one would expect based solely on structure evident in nongenetically informative data or lower resolution data. As follow-up, we make novel classifications of functional connections and examine highly localized connections with particularly strong genetic influence. This high-resolution genetic taxonomy of brain connectivity will be useful in understanding genetic influences on brain disorders.

The association between toddlerhood empathy deficits and antisocial personality disorder symptoms and psychopathy in adulthood.

The present study examined empathy deficits in toddlerhood (age 14 to 36 months) as predictors of antisocial personality disorder (ASPD) symptoms and psychopathy measured by the Levenson Self-Report Psychopathy scale (Levenson, Kiehl, & Fitzpatrick, 1995) in adulthood (age 23 years) in 956 individuals from the Colorado Longitudinal Twin Study. Consistent with the hypothesis that antisocial behavior is associated with "active" rather than "passive" empathy deficits, early disregard for others, not lack of concern for others, predicted later ASPD symptoms. Early disregard for others was also significantly associated with factor 1 of the Levenson Self-Report Psychopathy Scale, which includes items assessing interpersonal and affective deficits, but not with factor 2, which includes items assessing impulsivity and poor behavioral control. The association between early disregard for others and psychopathy factor 2 was near zero after controlling for the shared variance between psychopathy factors 1 and 2. These results suggest that there is a propensity toward adulthood ASPD symptoms and psychopathy factor 1 that can be assessed early in development, which may help identify individuals most at risk for stable antisocial outcomes.

Novel characterization of the multivariate genetic architecture of internalizing psychopathology and alcohol use.

Genetic correlations suggest that the genetic relationship of alcohol use with internalizing psychopathology depends on the measure of alcohol use. Problematic alcohol use (PAU) is positively genetically correlated with internalizing psychopathology, whereas alcohol consumption ranges from not significantly correlated to moderately negatively correlated with internalizing psychopathology. To explore these different genetic relationships of internalizing psychopathology with alcohol use, we performed a multivariate genome-wide association study of four correlated factors (internalizing psychopathology, PAU, quantity of alcohol consumption, and frequency of alcohol consumption) and then assessed genome-wide and local genetic covariance between these factors. We identified 14 significant regions of local, largely positive, genetic covariance between PAU and internalizing psychopathology and 12 regions of significant local genetic covariance (including both positive and negative genetic covariance) between consumption factors and internalizing psychopathology. Partitioned genetic covariance among functional annotations suggested that brain tissues contribute significantly to positive genetic covariance between internalizing psychopathology and PAU but not to the genetic covariance between internalizing psychopathology and quantity or frequency of alcohol consumption. We hypothesize that genome-wide genetic correlations between alcohol use and psychiatric traits may not capture the more complex shared or divergent genetic architectures at the locus or tissue specific level. This study highlights the complexity of genetic architectures of alcohol use and internalizing psychopathology, and the differing shared genetics of internalizing disorders with PAU compared to consumption.

The Latent Genetic Structure of Impulsivity and Its Relation to Internalizing Psychopathology.

Factor analyses suggest that impulsivity traits that capture tendencies to act prematurely or take risks tap partially distinct constructs. We applied genomic structure equation modeling to evaluate the genetic factor structure of two well-established impulsivity questionnaires, using published statistics from genome-wide association studies of up to 22,861 participants. We also tested the hypotheses that delay discounting would be genetically separable from other impulsivity factors and that emotionally triggered facets of impulsivity (urgency) would be those most strongly genetically correlated with an internalizing latent factor. A five-factor model best fitted the impulsivity data. Delay discounting was genetically distinct from these five factors. As expected, the two urgency subscales were most strongly related to an internalizing-psychopathology latent factor. These findings provide empirical genetic evidence that impulsivity can be broken down into distinct categories of differential relevance for internalizing psychopathology. They also demonstrate how measured genetic markers can be used to inform theories of psychology and personality.

Differential associations between rumination and intelligence subtypes.

Although prior theory suggests that rumination contributes to cognitive impairments associated with depression, recent work suggests that rumination is associated with higher levels of intelligence. The present study examined the relations between two ruminative subtypes (brooding and reflective pondering) and multiple measures and types of intelligence (verbal and performance) after controlling for rumination's overlapping variance with depression. Participants were 751 individuals from the Colorado Longitudinal Twin Study who completed the Ruminative Response Scale; the Center for Epidemiological Studies-Depression Scale and a fully structured clinical interview as measures of depression; and verbal and performance intelligence tasks at age 16 and the Raven's Advanced Progressive Matrices at age 23. Reflective pondering was positively associated with all measures of intelligence, whereas brooding was not associated with intelligence. Our findings indicate that any negative associations between rumination and intelligence are attributable to shared variance with depression, and that examination of rumination as a multifaceted construct may provide new insights into the relations between rumination and cognition.

Unity and diversity of executive functions in creativity.

Increasing evidence suggests that executive functions (EFs) - a set of general-purpose control processes that regulate thoughts and behaviors - are relevant for creativity. However, EF is not a unitary process, and it remains unclear which specific EFs are involved. The present study examined the association between the three EFs, both uniquely (EF-Specific) and together (Common EF), and three measures of creativity. Participants (N = 47) completed a divergent thinking test, and self-reported their real-life creative accomplishments. A subset of participants indicated their involvement in the artistic or information technology (IT) professions. Results indicated that fluency (but not originality) of divergent thinking was uniquely predicted by working memory Updating. Better response Inhibition predicted higher number of real-world artistic creative achievements. Involvement in the artistic (versus IT) professions was associated with better Common EF, and with enhanced mental set Shifting abilities. Results demonstrate that different EFs predict creativity depending on its operational definition.

A Longitudinal and Multidimensional Examination of the Associations Between Temperament and Self-Restraint During Toddlerhood.

Developing self-restraint, or the inhibition of behavior in response to a prohibition, is an important process during toddlerhood. The objective of this study was to gain a better understanding of individual differences in the development of self-restraint during toddlerhood by examining stable elements and growth of temperament (i.e., attentional control, behavioral inhibition, negative emotionality), general intelligence, and self-restraint. Participants were 412 same-sex twin pairs (approximately 90% European American) from predominately middle-class households in Colorado. Data were collected at 14, 20, 24, and 36 months. Results indicated that higher behavioral inhibition, attentional control, and intelligence were independently associated with better self-restraint, whereas higher negative emotionality was an independent predictor of lower self-restraint. The associations between temperament and self-restraint generally appeared to be stable from 14 to 36 months.

Etiology of Stability and Growth of Internalizing and Externalizing Behavior Problems Across Childhood and Adolescence.

Internalizing and externalizing behaviors are heritable, and show genetic stability during childhood and adolescence. Less work has explored how genes influence individual differences in developmental trajectories. We estimated ACE biometrical latent growth curve models for the Teacher Report Form (TRF) and parent Child Behavior Checklist (CBCL) internalizing and externalizing scales from ages 7 to 16 years in 408 twin pairs from the Colorado Longitudinal Twin Study. We found that Intercept factors were highly heritable for both internalizing and externalizing behaviors (a2 = .61-.92), with small and nonsignificant environmental influences for teacher-rated data but significant nonshared environmental influences for parent-rated data. There was some evidence of heritability of decline in internalizing behavior (Slopes for teacher and parent ratings), but the Slope genetic variance was almost entirely shared with that for the Intercept when different than zero. These results suggest that genetic effects on these developmental trajectories operate primarily on initial levels and stability, with no significant unique genetic influences for change. Finally, cross-rater analyses of the growth factor scores revealed moderate to large genetic and environmental associations between growth factors derived from parents' and teachers' ratings, particularly the Intercepts.

The Association Between Toddlerhood Self-Control and Later Externalizing Problems.

Lower self-control is a significant correlate or predictor of a wide range of adult outcomes, and this association may be due to more general tendencies toward childhood externalizing problems. The present study examined the association between toddlerhood self-control expressed within a "don't" compliance task (at 14-36 months) and later externalizing problems (parent-reported externalizing problems from age 4 to 12 years, teacher-reported externalizing problems from age 7 to 12 years, and self-reported conduct disorder symptoms at age 17 years) in a longitudinal, genetically informative study. The slope of self-control, but not its intercept, predicted later teacher-reported, but not parent- or self-reported, externalizing problems. That is, increase in self-control during toddlerhood was associated with lower levels of later teacher-reported externalizing problems. The slope of self-control was no longer a significant predictor of teacher-reported externalizing problems after controlling for observed disregard for others, a robust predictor of externalizing problems. Thus, the hypothesis that self-control is the primary predictor of externalizing problems was not supported. Results from genetic analyses suggested that the covariance between the slope of self-control and teacher-reported externalizing problems is due to both genetic and shared environmental influences.

Correlates of Positive Parenting Behaviors.

The present study examined the influence of maternal and child characteristics on parenting behaviors in a genetically informative study. The participants were 976 twins and their mothers from the Colorado Longitudinal Twin Study and the Twin Infant Project. Indicators of positive parenting were coded during parent-child interactions when twins were 7-36 months old. Child cognitive abilities and affection were independent correlates of positive parenting. There were significant gender differences in the magnitude of genetic and environmental influences on positive parenting, with shared environmental influences on parenting of girls and additive genetic influences on parenting of boys. Girls received significantly more positive parenting than boys. Differences in etiology of positive parenting may be explained by developmental gender differences in child cognitive abilities and affection, such that girls may have more rewarding interactions with parents, evoking more positive parenting.