Conduct disorder - a comprehensive exploration of comorbidity patterns, genetic and environmental risk factors.

Conduct disorder (CD), a common mental disorder in children and adolescents, is characterized by antisocial behavior. Despite similarities with antisocial personality disorder (ASPD) and possible diagnostic continuity, CD has been shown to precede a range of adult-onset mental disorders. Additionally, little is known about the putative shared genetic liability between CD and adult-onset mental disorders and the underlying gene-environment interplay. Here, we interrogated comorbidity between CD and other mental disorders from the Norwegian Mother, Father and Child Cohort Study (n = 114 500) and investigated how polygenic risk scores (PRS) for mental health traits were associated with CD/CD traits in childhood and adolescence. Gene-environment interplay patterns for CD was explored with data on bullying and parental education. We found CD to be comorbid with several child and adult-onset mental disorders. This phenotypic overlap corresponded with associations between PRS for mental disorders and CD. Additionally, our findings support an additive gene-environment model. Previously conceptualized as a precursor of ASPD, we found that CD was associated with polygenic risk for several child- and adult-onset mental disorders. High comorbidity of CD with other psychiatric disorders reflected on the genetic level should inform research studies, diagnostic assessments and clinical follow-up of this heterogenous group.

The association between delinquent peer affiliation and disruptive behavior interacts with functional brain correlates of reward sensitivity: a biosocial interaction study in adolescent delinquents.

BACKGROUND: Affiliating with delinquent peers may stimulate the development of antisocial behavior, especially for adolescents who are sensitive to social rewards. The current study examines whether the association between delinquent peer affiliation (DPA) and disruptive behavior interacts with functional brain correlates of reward sensitivity in early onset male adolescents delinquents. METHODS: Childhood arrestees (n = 126, mean age = 17.7 [s.d. 1.6]) completed a DPA questionnaire, and participated in an fMRI study in which reward sensitivity was operationalized through responsiveness of the ventral striatum (VS), amygdala, and medial prefrontal cortex (mPFC) during the monetary incentive delay paradigm (reward anticipation and outcome). Symptoms of disruptive behavior disorders (DBD) were assessed through structured psychiatric interviews (Diagnostic Interview Schedule for Children) with adolescents. RESULTS: DPA had a main effect on DBD symptoms. Adolescents with high VS reward responses showed a stronger significant positive association between DPA and DBD symptoms compared to low VS responders. No evidence for an interaction effect was found for the amygdala and mPFC. Post-hoc analyses revealed the positive association between DPA and DBD was only present in males, with a diminishing effect as age increased. CONCLUSIONS: We found evidence for a biosocial interaction between DPA and reward sensitivity of the VS in relation to DBD symptom severity. This study provides the first evidence of an interaction effect between a brain mechanism and an environmental factor in relation to DBD symptoms, implying that susceptibility to influences of delinquent peers may intertwine with individual biological differences.

Resting heart rate and antisocial behaviour: a Mendelian randomisation study.

Observational studies frequently report phenotypic associations between low resting heart rate (RHR) and higher levels of antisocial behaviour (ASB), although it remains unclear whether this relationship reflects causality. To triangulate evidence, we conducted two-sample univariable Mendelian randomisation (MR), multivariable MR and linkage disequilibrium score regression (LDSC) analyses. Genetic data were accessed from published genome-wide association studies (GWAS) for RHR (n = 458,835) and ASB (n = 85,359) for the univariable analyses, along with a third GWAS for heart rate variability (HRV; n = 53,174) for all other analyses. Genome-wide significant (p < 5 × 10-8) single-nucleotide polymorphisms associated with RHR (n = 278) were selected as instrumental variables and the outcome was a composite measure of ASB. No causal association was observed between RHR and ASB (BIVW = - 0.0004, p = 0.841). The multivariable MR analyses including RHR and HRV also suggested no causal associations (BIVW = 0.016, p = 0.914) and no genetic correlations between the heart rate measures and ASB were observed using LDSC (rg = 0.057, p = 0.169). Sensitivity analyses suggested that our results are not likely to be affected by heterogeneity, pleiotropic effects, or reverse causation. These findings suggest that individual differences in autonomic nervous system functioning indexed by RHR are not likely to directly contribute to the development of ASB. Therefore, previously observed associations between RHR and ASB may arise from confounding, reverse causation, and/or additional study characteristics. Further causally informative longitudinal research is required to confirm our findings, and caution should be applied when using measures of RHR in interventions targeting ASB.

A genetically informed Registered Report on adverse childhood experiences and mental health.

Children who experience adversities have an elevated risk of mental health problems. However, the extent to which adverse childhood experiences (ACEs) cause mental health problems remains unclear, as previous associations may partly reflect genetic confounding. In this Registered Report, we used DNA from 11,407 children from the United Kingdom and the United States to investigate gene-environment correlations and genetic confounding of the associations between ACEs and mental health. Regarding gene-environment correlations, children with higher polygenic scores for mental health problems had a small increase in odds of ACEs. Regarding genetic confounding, elevated risk of mental health problems in children exposed to ACEs was at least partially due to pre-existing genetic risk. However, some ACEs (such as childhood maltreatment and parental mental illness) remained associated with mental health problems independent of genetic confounding. These findings suggest that interventions addressing heritable psychiatric vulnerabilities in children exposed to ACEs may help reduce their risk of mental health problems.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

Shared genomic architectures of COVID-19 and antisocial behavior.

Little is known about the genetics of norm violation and aggression in relation to coronavirus disease 2019 (COVID-19). To investigate this, we used summary statistics from genome-wide association studies and linkage disequilibrium score regression to calculate a matrix of genetic correlations (rgs) for antisocial behavior (ASB), COVID-19, and various health and behavioral traits. After false-discovery rate correction, ASB was genetically correlated with COVID-19 (rg = 0.51; P = 1.54E-02) and 19 other traits. ASB and COVID-19 were both positively genetically correlated with having a noisy workplace, doing heavy manual labor, chronic obstructive pulmonary disease, and genitourinary diseases. ASB and COVID-19 were both inversely genetically correlated with average income, education years, healthspan, verbal reasoning, lifespan, cheese intake, and being breastfed as a baby. But keep in mind that rgs are not necessarily causal. And, if causal, their prevailing directions of effect (which causes which) are indiscernible from rgs alone. Moreover, the SNP-heritability ([Formula: see text]) estimates for two measures of COVID-19 were very small, restricting the overlap of genetic variance in absolute terms between ASB and COVID-19. Nonetheless, our findings suggest that those with antisocial tendencies possibly have a higher risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than those without antisocial tendencies. This may have been especially true early in the pandemic before vaccines against SARS-CoV-2 were available and before the emergence of the highly transmissible Omicron variant.

Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction.

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates.

Exploring the Genomic Architectures of Health, Physical Traits and Antisocial Behavioral Outcomes: A Brief Report.

A widely replicated finding across the behavioral sciences is that antisocial behaviors correlate with an array of health problems. Less clear, however, is the precise nature of this association. There is reason to suspect that a direct causal link exists between incarceration-a consequence of some antisocial behaviors-and certain negative health outcomes, for instance. However, it might be the case that broader phenotypes like antisocial behavior may correlate with certain health and physiological traits at a genomic level. We explore this possibility from a theoretical vantage point, while also presenting some preliminary data from existing secondary sources. Tentatively, no significant genetic correlations emerged across a host of health, physiological, and wellbeing outcomes after correction for multiple testing. However, more work is needed exploring this topic. We propose that future studies should make use of larger, more diverse samples and examine the genetic overlap between homogeneous clusters of antisocial behavioral subtypes and disease traits or symptoms.

Exploring the genetic correlations of antisocial behaviour and life history traits.

Prior evolutionary theory provided reason to suspect that measures of development and reproduction would be correlated with antisocial behaviours in human and non-human species. Behavioural genetics has revealed that most quantitative traits are heritable, suggesting that these phenotypic correlations may share genetic aetiologies. We use genome-wide association study data to estimate the genetic correlations between various measures of reproductive development (N = 52 776-318 863) and antisocial behaviour (N = 31 968). Our genetic correlation analyses demonstrate that alleles associated with higher reproductive output (number of children ever born, r g = 0.50, P = 0.0065) were positively correlated with alleles associated with antisocial behaviour, whereas alleles associated with more delayed reproductive onset (age at first birth, r g = -0.64, P = 0.0008) were negatively associated with alleles linked to antisocial behaviour. Ultimately, these findings coalesce with evolutionary theories suggesting that increased antisocial behaviours may partly represent a faster life history approach, which may be significantly calibrated by genes. DECLARATION OF INTEREST: None.

Genetic correlation of antisocial behaviour with alcohol, nicotine, and cannabis use.

BACKGROUND: There is high comorbidity between antisocial behaviour (ASB) and substance use, and twin studies have shown that part of the covariation is due to overlapping genetic influences. Here we used measured genetic effects to estimate the genetic correlations of ASB with nicotine, alcohol, and cannabis use. METHODS: We meta-analysed data from two genome-wide association studies for ASB and used existing summary statistics from the largest genome-wide association studies into substance use (ever smoking, cigarettes smoked per day, weekly alcohol consumption, and lifetime cannabis use). We performed cross-trait LD-score regression to estimate genetic correlations between ASB and substance use phenotypes explained by all single nucleotide polymorphisms (SNPs). When significant, we tested whether the signs of the regression coefficients of SNPs from the ASB and substance use phenotypes were in the same direction across multiple p-value thresholds and examined enrichment in overlap of the strongest associated SNPs. RESULTS: We found nominally significant genetic correlations of ASB with lifetime cannabis use (rg = 0.69, p=.016) and cigarettes per day (rg = 0.59, p = 0.036) but not with weekly alcohol consumption or ever smoking. Sign-tests revealed consistent directions of effect of SNPs for ASB and cannabis use for all p-value thresholds except the most stringent one, whereas for ASB with cigarettes per day no consistent evidence was found. We found no evidence of enrichment in overlap of the most associated SNPs across these traits. CONCLUSION: Using measured genetic variants, we found preliminary support for a genetic correlation of ASB with lifetime cannabis use and cigarettes per day.

The impact of chronic stress during adolescence on the development of aggressive behavior: A systematic review on the role of the dopaminergic system in rodents.

Pathological aggression, frequently observed in psychiatric patients and criminal subjects, poses a major burden on the health care and criminal justice system, necessitating better aetiological models to inform targets for prevention and intervention. Emerging evidence suggests that adverse experiences during development can cause long-lasting brain alterations associated with maladaptive behaviors, such as aggression. The present review discusses, mainly based on studies in rodents, whether disruption of the mesocorticolimbic dopamine system through chronic stress-exposure during adolescence predisposes to adult aggression. Our findings suggest that chronic stress in adolescence induces prefrontal cortex (PFC) hyperdopaminergia and ultimately leads to blunted prefrontal dopamine transmission in adulthood. This, in turn, disrupts the ability of the PFC to guide adaptive, long-term focused action selection by regulating mesolimbic dopamine signaling. We propose that, especially during the dynamic and transitional period of adolescence, exposure to chronic stress could lead to excessive adaptive change, which may result in an increased vulnerability to maladaptive aggression in adulthood. We discuss how these findings in rodents may translate to humans.

Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior.

Importance: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected. Conclusions and Relevance: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.

Meta-analysis of the serotonin transporter promoter variant (5-HTTLPR) in relation to adverse environment and antisocial behavior.

Several studies have suggested an association between antisocial, aggressive, and delinquent behavior and the short variant of the serotonin transporter gene polymorphism (5-HTTLPR). Yet, genome wide and candidate gene studies in humans have not convincingly shown an association between these behaviors and 5-HTTLPR. Moreover, individual studies examining the effect of 5-HTTLPR in the presence or absence of adverse environmental factors revealed inconsistent results. We therefore performed a meta-analysis to test for the robustness of the potential interaction effect of the "long-short" variant of the 5-HTTLPR genotype and environmental adversities, on antisocial behavior. Eight studies, comprising of 12 reasonably independent samples, totaling 7,680 subjects with an effective sample size of 6,724, were included in the meta-analysis. Although our extensive meta-analysis resulted in a significant interaction effect between the 5-HTTLPR genotype and environmental adversities on antisocial behavior, the methodological constraints of the included studies hampered a confident interpretation of our results, and firm conclusions regarding the direction of effect. Future studies that aim to examine biosocial mechanisms that influence the etiology of antisocial behavior should make use of larger samples, extend to genome-wide genetic risk scores and properly control for covariate interaction terms, ensuring valid and well-powered research designs. © 2016 Wiley Periodicals, Inc.

Unraveling the genetic etiology of adult antisocial behavior: a genome-wide association study.

Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS) on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10(-5)) was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies.

The covariation of trait anger and borderline personality: a bivariate twin-siblings study.

Anger can be defined as an emotion consisting of feelings of variable intensity, from mild irritation or annoyance to intense fury and rage. Borderline personality disorder (BPD) is characterized by impulsivity and instability of interpersonal relationships, of self-image, and of negative affects. Borderline personality and trait anger are often observed together. The present study examined the extent to which a genetic association explains the covariation between a trait measure of borderline personality and trait anger. To this end, self-report data of 5,457 twins and 1,487 of their siblings registered with the Netherlands Twin Register and the East Flanders Prospective Twin Survey were analyzed using genetic structural equation modeling. A significant phenotypic correlation was observed between the two traits (rP = .52). This correlation was explained by genetic (54%) and by environmental influences (46%). A shared genetic risk factor is thus one of the explanations for the covariation of borderline personality and trait anger.