Associations between polygenic risk of substance use and use disorder and alcohol, cannabis, and nicotine use in adolescence and young adulthood in a longitudinal twin study

Background Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset. Methods PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants (N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models. Results Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence. Conclusions PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.

Cortical and Subcortical Brain Volumes Partially Mediate the Association between Dietary Composition and Behavioral Disinhibition: A UK Biobank Study

Behavioral disinhibition is observed to be an important characteristic of many neurodevelopmental and psychiatric disorders. Recent studies have linked dietary quality to levels of behavioral inhibition. However, it is currently unclear whether brain factors might mediate this. The current study investigates whether cortical and subcortical brain volumes mediate part of the association between dietary composition and behavioral disinhibition. A total of 15,258 subjects from the UK Biobank project were included in the current study. Dietary composition and behavioral disinhibition were based on Principle Component Analyses of self-reported dietary composition). As a further data reduction step, cortical and subcortical volume segmentations were input into an Independent Component Analysis. The resulting four components were used as mediator variables in the main mediation analyses, where behavioral disinhibition served as the outcome variable and dietary components as predictors. Our results show: (1) significant associations between all dietary components and brain volume components; (2) brain volumes are associated with behavioral disinhibition; (3) the mediation models show that part of the variance in behavioral disinhibition explained by dietary components (for healthy diet, restricted diet, and high-fat dairy diet) is mediated through the frontal-temporal/parietal brain volume component. These results are in part confirming our hypotheses and offer a first insight into the underlying mechanisms linking dietary composition, frontal-parietal brain volume, and behavioral disinhibition in the general adult population.

What Do We Mean by Behavioral Disinhibition in Frontotemporal Dementia?

Behavioral variant frontotemporal dementia, unlike other forms of dementia, is primarily characterized by changes in behavior, personality, and language, with disinhibition being one of its core symptoms. However, because there is no single definition that captures the totality of behavioral symptoms observed in these patients, disinhibition is an umbrella term used to encompass socially disruptive or morally unacceptable behaviors that may arise from distinct neural etiologies. This paper aims to review the current knowledge about behavioral disinhibition in this syndrome, considering the cultural factors related to our perception of behavior, the importance of phenomenological interpretation, neuroanatomy, the brain networks involved and, finally, a new neuroscientific theory that offers a conceptual framework for understanding the diverse components of behavioral disinhibition in this neurodegenerative disorder.

Relationship between benzodiazepine prescription, aggressive behavior, and behavioral disinhibition: a retrospective study in a Swiss prison

Background Benzodiazepines are commonly prescribed in prisons amidst the controversies surrounding their potential role in causing behavioral disinhibition and aggressive behavior and their association with use and trafficking of illicit and addictive substances. The present study aimed to (1) ascertain the relationship between benzodiazepine prescription (including their dosage and duration of use) and aggressive behavior and behavioral disinhibition in prison and (2) investigate whether there was an association between benzodiazepine prescription, (including their dosage and duration of use) and using and trafficking illicit and addictive substances during imprisonment. Methods Data were extracted from the electronic database of an “open” Swiss prison (n = 1206, 1379 measures) over a 5-year period (2010–2015). Measures included benzodiazepine prescription, duration of benzodiazepine use and mean dosage, and punishable behaviors (physical and verbal aggression, disinhibited but not directly aggressive behaviors, property damage or theft, substance-related offenses, and rule transgression). We assessed the relationship between benzodiazepine prescription and punishable behaviors after propensity score matching. Logistic regressions were also used to test the relationship of benzodiazepine use duration and dosage with punishable behaviors among participants who received benzodiazepines. Results After propensity score matching, benzodiazepine prescription was not significantly associated with any punishable behavior. Among detained persons who took benzodiazepines, there was no significant association of dosage and duration of use with offenses involving illicit or addictive substance use or trafficking. Conclusions Our study did not empirically support the occurrence of increased aggressive or disinhibited behaviors or increased risk of substance abuse in detained persons who received benzodiazepines in prison. This suggests a need to reconsider restrictions in prescribing benzodiazepines in the prison setting.

Polygenic Score for Smoking Is Associated With Externalizing Psychopathology and Disinhibited Personality Traits but Not Internalizing Psychopathology in Adolescence

We examined whether a polygenic score (PGS) for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits at multiple time points in adolescence (ages 11, 14, and 17 years; N = 3,225). The smoking PGS had strong associations with the stable variance across time for all the externalizing measures (mean standardized β = 0.27), agreeableness (β = −0.22, 95% confidence interval [CI] = [−0.28, −0.16]), and conscientiousness (β = −0.19, 95% CI = [−0.24, −0.13]) but was not significantly associated with internalizing measures (mean β = 0.06) or extraversion (β = 0.01, 95% CI = [−0.05, 0.07]). After controlling for smoking at age 17 years, the associations with externalizing, low agreeableness, and low conscientiousness remained statistically significant. The smoking PGS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition, including externalizing psychopathology and normal-range personality traits related to behavioral control but not internalizing psychopathology.

Polygenic Scores for Smoking and Educational Attainment have Independent Influences on Academic Success and Adjustment in Adolescence and Educational Attainment in Adulthood

Educational success is associated with greater quality of life and depends, in part, on heritable cognitive and non-cognitive traits. We used polygenic scores (PGS) for smoking—a measure of genetic influences on behavioral disinhibition—and educational attainment to examine different genetic influences on facets of academic adjustment in adolescence and educational attainment in adulthood. PGSs were calculated for participants of the Minnesota Twin Family Study (N = 3225) and included as predictors of grades, academic motivation, and discipline problems at ages 11, 14, and 17 years-old and educational attainment at age 29. Smoking and educational attainment PGSs had significant incremental associations with each academic variable. About half of the adjusted effects of the smoking and educational PGSs on educational attainment at age 29 were mediated by the academic variables in adolescence. Distinct genetic influences related to behavioral disinhibition and educational attainment contribute to academic adjustment in adolescence and educational attainment in adulthood.

Relationship Between Benzodiazepine Prescription, Aggressive Behavior, and Behavioral Disinhibition: A Case-control Study in a Swiss Prison

Background. Benzodiazepines are commonly prescribed in prisons amidst the controversies surrounding their potential role in causing behavioral disinhibition and aggressive behavior and their association with use and trafficking of illicit and addictive substances. The present study aimed to 1) ascertain the relationship between benzodiazepine prescription (including their dosage and duration of use) and aggressive behavior and behavioral disinhibition in prison, and 2) investigate whether there was an association between benzodiazepine prescription, (including their dosage and duration of use) and using and trafficking illicit and addictive substances during imprisonment. Methods. Data were extracted from the electronic database of an “open” Swiss prison (n = 1,379) over a five-year period (2010–2015). Measures included benzodiazepine prescription (yes/no), duration of benzodiazepine use and mean dosage, and punishable behaviors (physical and verbal aggression, disinhibited but not directly aggressive behaviors, property damage or theft, substance-related offenses, and rule transgression). Propensity score matching was used to assess the relationship between benzodiazepine prescription and punishable behaviors. Logistic regressions were used to test the relationship of benzodiazepine duration and dosage with punishable behaviors. Results. Benzodiazepine prescription (yes/no) was not significantly associated with punishable behaviors. Detained persons taking benzodiazepines were not more likely to commit offenses involving illicit or addictive substance use or trafficking, even when taking these medications in higher dosage and over a longer period of time. Conclusions. Our findings suggest that access to benzodiazepines in the prison setting should be subject to the same regulations as in the community and that prescribing benzodiazepines to detained persons is just as safe as prescribing these medications to those who are not detained.

Polygenic Risk Score for Smoking is associated with Externalizing Psychopathology and Disinhibited Personality Traits but not Internalizing Psychopathology in Adolescence

ImportanceLarge consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk.ObjectiveWe examined whether a PRS for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality.MethodsRandom intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225).ResultsThe smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized β = .27), agreeableness (β=−.22, 95% CI: −.28, −.16), and conscientiousness (β=−.19, 95% CI: −.24, −.13), but was not significantly associated with the internalizing measures (mean β = .06) or extraversion (β=.01, 95% CI: −.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean β = .13) and personality traits related to behavioral control (mean β = −.10) remained statistically significant.Conclusions and RelevanceThe smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition including externalizing psychopathology and normal-range personality traits related to behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality).Key PointsQuestionDoes a polygenic risk scores (PRS) for smoking measure genetic risk for behavioral disinhibition in general?FindingsThe smoking PRS was associated with externalizing psychopathology and personality traits related to behavioral control, but not internalizing psychopathology and extraversion during adolescence, even after controlling for smoking status.MeaningThe smoking PRS measures genetic influences on behavioral disinhibition in general which is associated with a variety of important outcomes including mental health, academic success, and criminality.

Polygenic Risk Score for Smoking is associated with Externalizing Psychopathology and Disinhibited Personality Traits but not Internalizing Psychopathology in Adolescence

Importance: Large consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk. Objective: We examined whether a PRS for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality. Methods: Random intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225). Results: The smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized ꞵ = .27), agreeableness (ꞵ=-.22, 95% CI: -.28, -.16), and conscientiousness (ꞵ=-.19, 95% CI: -.24, -.13), but was not significantly associated with the internalizing measures (mean ꞵ = .06) or extraversion (ꞵ=.01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean ꞵ = .13) and personality traits related to behavioral control (mean ꞵ = -.10) remained statistically significant. Conclusions and Relevance: The smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition including externalizing psychopathology and normal-range personality traits related to behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality).