Shared Genetic Influences Between Loss-of-Control Eating and Body Mass Index in Adolescent Twins.

OBJECTIVE: Pediatric loss-of-control (LOC) eating is associated with high BMI and predicts binge-eating disorder and obesity onset with age. Research on the etiology of this common comorbidity has not explored the potential for shared genetic risk. This study examined genetic and environmental influences on LOC eating and its shared influence with BMI. METHOD: Participants were 499 monozygotic and 398 same-sex dizygotic twins (age = 17.38 years ± 0.67, BMIz = 0.03 ± 1.03, 54% female) from the Colorado Center for Antisocial Drug Dependence Study. LOC eating was assessed dichotomously. Self-reported height and weight were converted to BMIz. Univariate and bivariate twin models estimated genetic and environmental influences on LOC eating and BMIz. RESULTS: More girls (21%) than boys (9%, p < 0.001) reported LOC eating. The phenotypic correlation with BMIz was 0.03 in girls and 0.18 in boys. Due to the nonsignificant phenotypic correlation in girls, bivariate twin models were fit in boys only. Across all models, the best-fitting model included genetic and unique environmental effects. Genetic factors accounted for 0.51 (95% CI: 0.23, 0.73) of the variance of LOC eating in girls and 0.54 (0.18, 0.90) in boys. The genetic correlation between LOC eating and BMIz in boys was 0.45 (0.15, 0.75). DISCUSSION: Findings indicate moderate heritability of LOC eating in adolescence, while emphasizing the role of unique environmental factors. In boys, LOC eating and BMIz share a proportion of their genetic influences.

Recreational cannabis legalization has had limited effects on a wide range of adult psychiatric and psychosocial outcomes.

BACKGROUND: The causal impacts of recreational cannabis legalization are not well understood due to the number of potential confounds. We sought to quantify possible causal effects of recreational cannabis legalization on substance use, substance use disorder, and psychosocial functioning, and whether vulnerable individuals are more susceptible to the effects of cannabis legalization than others. METHODS: We used a longitudinal, co-twin control design in 4043 twins (N = 240 pairs discordant on residence), first assessed in adolescence and now age 24-49, currently residing in states with different cannabis policies (40% resided in a recreationally legal state). We tested the effect of legalization on outcomes of interest and whether legalization interacts with established vulnerability factors (age, sex, or externalizing psychopathology). RESULTS: In the co-twin control design accounting for earlier cannabis frequency and alcohol use disorder (AUD) symptoms respectively, the twin living in a recreational state used cannabis on average more often (ßw = 0.11, p = 1.3 × 10-3), and had fewer AUD symptoms (ßw = -0.11, p = 6.7 × 10-3) than their co-twin living in an non-recreational state. Cannabis legalization was associated with no other adverse outcome in the co-twin design, including cannabis use disorder. No risk factor significantly interacted with legalization status to predict any outcome. CONCLUSIONS: Recreational legalization was associated with increased cannabis use and decreased AUD symptoms but was not associated with other maladaptations. These effects were maintained within twin pairs discordant for residence. Moreover, vulnerabilities to cannabis use were not exacerbated by the legal cannabis environment. Future research may investigate causal links between cannabis consumption and outcomes.

Genotype Data and Derived Genetic Instruments of Adolescent Brain Cognitive Development Study® for Better Understanding of Human Brain Development.

The data release of Adolescent Brain Cognitive Development® (ABCD) Study represents an extensive resource for investigating factors relating to child development and mental wellbeing. The genotype data of ABCD has been used extensively in the context of genetic analysis, including genome-wide association studies and polygenic score predictions. However, there are unique opportunities provided by ABCD genetic data that have not yet been fully tapped. The diverse genomic variability, the enriched relatedness among ABCD subsets, and the longitudinal design of the ABCD challenge researchers to perform novel analyses to gain deeper insight into human brain development. Genetic instruments derived from the ABCD genetic data, such as genetic principal components, can help to better control confounds beyond the context of genetic analyses. To facilitate the use genomic information in the ABCD for inference, we here detail the processing procedures, quality controls, general characteristics, and the corresponding resources in the ABCD genotype data of release 4.0.

Exploring Relationships Between Internalizing Problems and Risky Sexual Behavior: A Twin Study.

Previous research links risky sexual behavior (RSB) to externalizing problems and to substance use, but little research has been conducted on relationships between internalizing problems (INT) and RSB. The current study addresses that literature gap, using both a twin sample from Colorado (N = 2567) and a second twin sample from Minnesota (N = 1131) in attempt to replicate initial results. We explored the hypothesis that the latent variable INT would be more strongly associated with the latent variable RSB for females than for males, examining relationships between INT and RSB via phenotypic confirmatory factor analysis and multivariate twin analyses. We found a small but significant phenotypic association between the latent variables. However, despite using two large twin samples, limited power restricted our ability to identify the genetic and environmental mechanisms underlying this association. Our sex differences hypothesis was not fully supported in either sample and requires further investigation. Our findings illustrate the complexity of the relationship between internalizing problems and risky sexual behavior.

Genetic and Environmental Variation in Continuous Phenotypes in the ABCD Study®.

Twin studies yield valuable insights into the sources of variation, covariation and causation in human traits. The ABCD Study® (abcdstudy.org) was designed to take advantage of four universities known for their twin research, neuroimaging, population-based sampling, and expertise in genetic epidemiology so that representative twin studies could be performed. In this paper we use the twin data to: (i) provide initial estimates of heritability for the wide range of phenotypes assessed in the ABCD Study using a consistent direct variance estimation approach, assuring that both data and methodology are sound; and (ii) provide an online resource for researchers that can serve as a reference point for future behavior genetic studies of this publicly available dataset. Data were analyzed from 772 pairs of twins aged 9-10 years at study inception, with zygosity determined using genotypic data, recruited and assessed at four twin hub sites. The online tool provides twin correlations and both standardized and unstandardized estimates of additive genetic, and environmental variation for 14,500 continuously distributed phenotypic features, including: structural and functional neuroimaging, neurocognition, personality, psychopathology, substance use propensity, physical, and environmental trait variables. The estimates were obtained using an unconstrained variance approach, so they can be incorporated directly into meta-analyses without upwardly biasing aggregate estimates. The results indicated broad consistency with prior literature where available and provided novel estimates for phenotypes without prior twin studies or those assessed at different ages. Effects of site, self-identified race/ethnicity, age and sex were statistically controlled. Results from genetic modeling of all 53,172 continuous variables, including 38,672 functional MRI variables, will be accessible via the user-friendly open-access web interface we have established, and will be updated as new data are released from the ABCD Study. This paper provides an overview of the initial results from the twin study embedded within the ABCD Study, an introduction to the primary research domains in the ABCD study and twin methodology, and an evaluation of the initial findings with a focus on data quality and suitability for future behavior genetic studies using the ABCD dataset. The broad introductory material is provided in recognition of the multidisciplinary appeal of the ABCD Study. While this paper focuses on univariate analyses, we emphasize the opportunities for multivariate, developmental and causal analyses, as well as those evaluating heterogeneity by key moderators such as sex, demographic factors and genetic background.

Anxiety-specific associations with substance use: Evidence of a protective factor in adolescence and a risk factor in adulthood.

Externalizing psychopathology is a strong risk factor for substance use, whereas the role of internalizing manifestations of distress, and anxiety in particular, in predicting substance use remains unclear. Studies have suggested that anxiety may be either a protective or risk factor for substance use. The present study aimed to clarify evidence for anxiety-specific associations with substance use, examining sex and developmental period (adolescence vs. adulthood) as potential moderators that may help explain conflicting results in the literature. In a longitudinal twin sample, cross-sectional associations of anxiety with substance use differed in adolescents and adults and in girls/women and boys/men. Controlling for externalizing psychopathology and depression, anxiety was associated with reduced substance use in adolescent girls and increased substance use in adult women. In contrast, anxiety-specific associations with substance use were not significant in boys and men. Possible explanations for these contrasting results across development and sex are discussed.

Evaluating substance use outcomes of recreational cannabis legalization using a unique co-twin control design.

Background: As more states pass recreational cannabis legalization (RCL), we must understand how RCL affects substance use.Objectives: The current study aims to examine the effect of RCL on lifetime and past-year use of cannabis, alcohol, tobacco, and other drugs, frequency of cannabis, alcohol, and tobacco use, co-use of cannabis with alcohol and tobacco, and consequences from cannabis and alcohol use.Methods: We used a unique, co-twin control design of twin pairs who were discordant for living in a state with RCL between 2018 and 2021. The sample consisted of 3,830 adult twins (41% male), including 232 twin pairs discordant for RCL. Problems from alcohol and cannabis use were assessed via the Brief Marijuana Consequences Questionnaire and the Brief Young Adult Alcohol Consequences Questionnaire.Results: Results indicated that the twin living in an RCL state was more likely to endorse past-year cannabis use (OR = 1.56, p = .009), greater number of cannabis use days in the past 6 months (ß = 0.47, p = .019), but not more negative consequences from cannabis use (ß = 0.21, p = .456) compared to their co-twin in a non-RCL state. There were no differences within-twin pairs in frequency of alcohol use (ß=-0.05, p = .601), but the RCL twin reported fewer negative consequences from alcohol use (ß=-0.29, p = .016) compared to their co-twin in a non-RCL state. We did not observe any other differences within-twin pairs on other outcomes.Conclusion: These results suggest that living in an RCL state is associated with greater cannabis frequency but not more negative consequences from cannabis use than living in a non-RCL state.

Addendum to "Evaluating substance use outcomes of recreational cannabis legalization using a unique co-twin control design".

An earlier version of this article was published in error. Our prior publication was missing reference to a prior study on this topic. Our prior research has not found an association between recreational cannabis legalization (RCL) and negative psychosocial and psychiatric outcomes. We reported significant associations between RCL with greater cannabis frequency and fewer alcohol use disorder symptoms. The current study expands on our previous research by using a cross-sectional design and different measures of problems from cannabis and alcohol use and including additional substance use variables. The current study found similar results to our previous research.

The association between saving disposition and financial distress: A genetically informed approach.

Saving disposition, the tendency to save rather than consume, has been found to be associated with economic outcomes. People lacking the disposition to save are more likely to experience financial distress. This association could be driven by other economic factors, behavioral traits, or even genetic effects. Using a sample of 3,920 American twins, we develop scales to measure saving disposition and financial distress. We find genetic influences on both traits, but also a large effect of the rearing family environment on saving disposition. We estimate that 44% of the covariance between the two traits is due to genetic effects. Saving disposition remains strongly associated with lower financial distress, even after controlling for family income, cognitive ability, and personality traits. The association persists within families and monozygotic twin pairs; the twin who saves more tends to be the twin who experiences less financial distress. This result suggest that there is a direct association between saving disposition and financial distress, although the direction of causation remains unclear.

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.

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.

Etiological Overlap Between Sex Under the Influence and Number of Lifetime Sexual Partners.

Drug and alcohol use is associated with risky sexual behavior (RSB). It is unclear whether this association is due to correlated liabilities (e.g., third variables influencing both traits), or whether use of drugs and alcohol during sexual decision making increases RSB. This study addresses this question by fitting a series of biometrical models using over 800 twin pairs assessed in early adulthood (m = 25.21 years). Measures included an index of sex under the influence (e.g., frequency that drugs or alcohol affect sexual decision making), number of lifetime sexual partners, and a general measure of substance use. Analyses suggest the covariance among these measures is explained by both genetic and environmental correlated liabilities. The overlap was not specific to sex under the influence, but was shared with a measure of general substance use. Models testing necessary but not sufficient parameters for direction of causation suggest that sex under the influence is unlikely to cause an increase in RSB; more evidence for reverse causation was found.

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

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.

Proper conditional analysis in the presence of missing data: Application to large scale meta-analysis of tobacco use phenotypes.

Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e. the summary association statistics are measured for all variants in contributing studies. In practice, genotype imputation is not always effective. This may be the case when targeted genotyping/sequencing assays are used or when the un-typed genetic variant is rare. Therefore, contributed summary statistics often contain missing values. Existing methods for imputing missing summary association statistics and using imputed values in meta-analysis, approximate conditional analysis, or simple strategies such as complete case analysis all have theoretical limitations. Applying these approaches can bias genetic effect estimates and lead to seriously inflated type-I or type-II errors in conditional analysis, which is a critical tool for identifying independently associated variants. To address this challenge and complement imputation methods, we developed a method to combine summary statistics across participating studies and consistently estimate joint effects, even when the contributed summary statistics contain large amounts of missing values. Based on this estimator, we proposed a score statistic called PCBS (partial correlation based score statistic) for conditional analysis of single-variant and gene-level associations. Through extensive analysis of simulated and real data, we showed that the new method produces well-calibrated type-I errors and is substantially more powerful than existing approaches. We applied the proposed approach to one of the largest meta-analyses to date for the cigarettes-per-day phenotype. Using the new method, we identified multiple novel independently associated variants at known loci for tobacco use, which were otherwise missed by alternative methods. Together, the phenotypic variance explained by these variants was 1.1%, improving that of previously reported associations by 71%. These findings illustrate the extent of locus allelic heterogeneity and can help pinpoint causal variants.

Children's Knowledge of Cannabis and Other Substances in States with Different Cannabis Use Regulations.

Background: Public acceptance of cannabis continues to increase across the US, yet there has been little research on how cannabis legalization affects young children. The present study compared knowledge of cannabis and other substances among children living in states with different cannabis laws and examined whether the association between such substance knowledge and externalizing behavior varies by state cannabis regulations. Methods: Participants were from the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) at the baseline assessment (N = 11,875, ages 9-11, collected from 2016 to 2018). Chi-square difference tests were used to compare nested models testing group differences in knowledge of substances and the association between externalizing disorder/behavior and substance knowledge as a function of state legality of cannabis use (recreational, medical, low THC/CBD, none). Results: Children living in states with more permissive cannabis laws had a greater knowledge of cannabis and reported more alcohol experimentation. In contrast, knowledge regarding alcohol, tobacco, and other illicit drugs was not greater in children from states with more permissive cannabis laws. Externalizing disorder/behavior was not significantly associated with cannabis knowledge in any group and not significantly different across groups. The association between externalizing disorder/behavior and illicit drug knowledge was significant only in states with the recreational and medical use laws but did not differ significantly across groups. Conclusion: Children living in environments with more permissive cannabis regulations have greater knowledge of cannabis, but not other substances, and report more experimentation with alcohol.

Adolescent Externalizing Psychopathology and Its Prospective Relationship to Marijuana Use Development from Age 14 to 30: Replication Across Independent Longitudinal Twin Samples.

Externalizing psychopathology in early adolescence is a highly heritable risk factor for drug use, yet how it relates to marijuana use development is not well-characterized. We evaluate this issue in independent twin samples from Colorado (N = 2608) and Minnesota (N = 3630), assessed from adolescence to early adulthood. We used a biometric latent growth model of marijuana use frequency with data from up to five waves of assessment from ages 14 to 30, to examine change in marijuana use and its relationship with a factor model of adolescent externalizing psychopathology. The factor structure of adolescent externalizing psychopathology was similar across samples, as was the association between that common factor and early marijuana use (Minnesota r = 0.67 [0.60, 0.75]; Colorado r = 0.69 [0.59, 0.78]), and increase in use (Minnesota r = 0.18 [0.10, 0.26]; Colorado r = 0.20 [0.07, 0.34]). Early use was moderately heritable in both samples (Minnesota h2 = 0.57 [0.37, 0.79]; Colorado h2 = 0.42 [0.14, 0.73]). Increase in use was highly heritable in Minnesota (h2 = 0.82 [0.72, 0.88]), less so in Colorado (h2 = 0.22 [0.01, 0.66]), and shared environmental effects were larger in Colorado (c2 = 0.55 [0.14, 0.83]) than Minnesota (c2 = 0 [0, 0.06]). We found moderate genetic correlations between externalizing psychopathology and early use in both samples. Finally, additional analyses in the Minnesota sample indicated that marijuana use decreased during the late 20s. This decline is strongly heritable (h2 = 0.73 [0.49, 0.91]) and moderately negatively correlated with adolescent externalizing psychopathology (r = - 0.41 [- 0.54, - 0.28]). Adolescent externalizing psychopathology is genetically correlated with change in late adolescent marijuana use (late teens, early 20s), as well as maintenance of use in early adulthood (late 20 s) even after controlling for the effects of early use.

The Role of A Priori-Identified Addiction and Smoking Gene Sets in Smoking Behaviors.

INTRODUCTION: Smoking is a leading cause of death, and genetic variation contributes to smoking behaviors. Identifying genes and sets of genes that contribute to risk for addiction is necessary to prioritize targets for functional characterization and for personalized medicine. METHODS: We performed a gene set-based association and heritable enrichment study of two addiction-related gene sets, those on the Smokescreen Genotyping Array and the nicotinic acetylcholine receptors, using the largest available GWAS summary statistics. We assessed smoking initiation, cigarettes per day, smoking cessation, and age of smoking initiation. RESULTS: Individual genes within each gene set were significantly associated with smoking behaviors. Both sets of genes were significantly associated with cigarettes per day, smoking initiation, and smoking cessation. Age of initiation was only associated with the Smokescreen gene set. Although both sets of genes were enriched for trait heritability, each accounts for only a small proportion of the single nucleotide polymorphism-based heritability (2%-12%). CONCLUSIONS: These two gene sets are associated with smoking behaviors, but collectively account for a limited amount of the genetic and phenotypic variation of these complex traits, consistent with high polygenicity. IMPLICATIONS: We evaluated evidence for the association and heritable contribution of expert-curated and bioinformatically identified sets of genes related to smoking. Although they impact smoking behaviors, these specifically targeted genes do not account for much of the heritability in smoking and will be of limited use for predictive purposes. Advanced genome-wide approaches and integration of other 'omics data will be needed to fully account for the genetic variation in smoking phenotypes.

Nick Martin and the 'Boulder Workshops'.

The author provides a personal perspective on Nick Martin's contributions to behavioral genetics and his role in the workshops on statistical genetics held annually in Boulder. Highlighted are Prof. Martin's seminal work on multivariate behavioral genetics, his career-long commitment to the value of the study of twins, and his enthusiastic support of the didactic mission of the 'Boulder workshops'. These contributions and activities continue unabated as we celebrate Prof. Martin's 70th birthday.