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Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P

Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p = 0.06). Gene-based tests identified seven genes associated with BD (p ≤ 2.0 × 10−6). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD.

Previous studies have shown associations between single nucleotide polymorphisms (SNPs) in gamma aminobutyric acid receptor alpha 2 (GABRA2) and adolescent conduct disorder (CD) and alcohol dependence in adulthood, but not adolescent alcohol dependence. The present study was intended as a replication and extension of this work, focusing on adolescent CD, adolescent alcohol abuse and dependence (AAD), and adult AAD. Family based association tests were run using Hispanics and non-Hispanic European American subjects from two independent longitudinal samples. Although the analysis provided nominal support for an association with rs9291283 and AAD in adulthood and CD in adolescence, the current study failed to replicate previous associations between two well replicated GABRA2 SNPs and CD and alcohol dependence. Overall, these results emphasize the utility of including an independent replication sample in the study design, so that the results from an individual sample can be weighted in the context of its reproducibility. © 2014 Springer Science+Business Media New York.

Objective: Childhood maltreatment is a potent risk factor for subsequent aggressive and criminal behavior. A recent study suggested that the relationship between maltreatment and antisocial behavior may be moderated by a genetic vulnerability conferred by a functional polymorphism in the MAO-A gene. The authors investigated whether these findings would generalize to a clinical cohort of adolescents, examining whether there was a stronger association between maltreatment and conduct disorder severity in patients carrying the low MAO-A activity allele.Method: Male adolescent patients (N=247) entering residential or intensive day treatment for persistent conduct and substance use problems were examined. Conduct disorder severity was indexed by a lifetime count of DSM-IV criteria obtained through structured psychiatric interviews. Maltreatment scores were derived from summing neglect and abuse events reported to have occurred before age 11.Results: Neglect, verbal/psychological abuse, physical abuse, and sexual abuse were prevalent among patients. Although level of maltreatment and lifetime conduct disorder symptoms were significantly correlated, no genetic-environmental interaction with genotype for maltreatment was found.Conclusion: The results of the current study do not support the hypothesis that a polymorphism in the gene encoding MAO-A contributes to the genetic risk for conduct disorder. [ABSTRACT FROM AUTHOR]

This study describes results from a genome-wide search for quantitative trait loci (QTL) influencing substance dependence vulnerability in adolescence. We utilized regression-based multipoint (and single-point) QTL mapping procedures designed for selected sibpair samples. Selected sibling pairs included 250 proband-sibling pairs from 192 families. Clinical probands (13-19 years of age) were drawn from consecutive admissions to substance abuse treatment facilities in the Denver metropolitan area; siblings of probands ranged in age from 12 to 25 years. In addition to the selected sample, a community-based sample of 3676 adolescents and young adults were utilized to define a clinically-significant, heritable, age- and sex-normed index of substance dependence vulnerability-a priori and independent of our linkage results. Siblings and their parents were genotyped for 374 STR micro-satellite markers distributed across the 22 autosomes (average inter-marker distance=9.2 cM). Non-parametric single-point linkage results indicated 17 markers on 11 chromosomes with nominally significant tests of linkage; six markers with LOD scores greater than 1.0 and one marker (D3S1614) with a LOD score of 2.2. Multipoint mapping corroborated two locations and provided preliminary evidence for linkage to regions on chromosome 3q24-25 (near markers D3S1279 and D3S1614) and chromosome 9q34 (near markers D9S1826 and D9S1838). [ABSTRACT FROM AUTHOR]

We present data on the lifetime prevalence of substance use, abuse and dependence in adolescents obtained through structured psychiatric interviews and self-report questionnaires. Most notably, we evaluate symptom profiles based on DSM-IV abuse and dependence criteria for tobacco, alcohol and marijuana, including a gender comparison. Participants are 3,072 adolescents (12-18 years) drawn from three community-based family samples in Colorado. Age trends suggest that substance use is a developmental phenomenon, which increases almost linearly from early to late adolescence. Substance use disorders are less common than experimentation in adolescence, but approximately 1 in 4 adolescents in the oldest cohorts meets criteria for abuse for at least one substance, and 1 in 5 meets criteria for substance dependence. By age 18 nearly 1 in 3 adolescents report daily smoking and 8.6% meet criteria for tobacco dependence. Although alcohol is the most commonly abused substance (10%), a slightly larger proportion of adolescents meet criteria for dependence on marijuana (4.3%) than alcohol (3.5%). Gender differences in prevalence of use more often show greater use in males than females. Males more frequently meet criteria for dependence on alcohol and marijuana in late adolescence, while females are more often nicotine dependent. A comparison of abuse and dependence symptom profiles shows some interesting variability across substances, and suggests that manifestations of a subset of symptoms are gender specific. [ABSTRACT FROM AUTHOR]

Risky sexual behavior (RSB) has been linked to externalizing problems, substance use, and, in a recent study by our lab, internalizing problems. The current study builds upon previous work investigating the relationship between RSB and internalizing problems (INT) by controlling for externalizing problems (EXT) to account for the correlation between INT and EXT. We used a twin sample from Colorado (N = 2,544) to investigate phenotypic and genetic relationships between the three latent constructs, as well as potential sex differences in those relationships. We hypothesized that the relationship between RSB and INT would be stronger for females than for males, whereas the relationship between RSB and EXT would be stronger for males than for females. We used phenotypic confirmatory factor analysis and multivariate twin analyses to address research questions. Our results show significant phenotypic relationships among RSB, INT, and EXT and provide modest evidence in males for a significant association between RSB and INT that persists when controlling for EXT, a finding which we interpret with caution. Our sex differences hypothesis was not fully supported, although the direction of effects was in the direction hypothesized for the association between RSB and INT. We discuss the complexity of RSB as a phenotype and the potential implications for public health., Competing Interests: Declarations Ethics Approval All procedures were approved by institutional review boards at the site of data collection and comply with the World Medical Association Declaration of Helsinki. The site’s institutional review boards have indicated that analyses using the retrospective, anonymized data are not human subjects research and do not require their own approval. Consent to Participate Consent to participate was provided at the time of original data collection. Consent for Publication Consent for publication was provided at the time of original data collection. Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2024 Wiley Periodicals LLC.)

Externalizing behaviors encompass manifestations of risk-taking, self-regulation, aggression, sensation-/reward-seeking, and impulsivity. Externalizing research often includes substance use (SUB), substance use disorder (SUD), and other (non-SUB/SUD) "behavioral disinhibition" (BD) traits. Genome-wide and twin research have pointed to overlapping genetic architecture within and across SUB, SUD, and BD. We created single-factor measurement models-each describing SUB, SUD, or BD traits-based on mutually exclusive sets of European ancestry genome-wide association study (GWAS) statistics exploring externalizing variables. We then assessed the partitioning of genetic covariance among the three facets using correlated factors models and Cholesky decomposition. Even when the residuals for indicators relating to the same substance were correlated across the SUB and SUD factors, the two factors yielded a large correlation (r g  = 0.803). BD correlated strongly with the SUD (r g  = 0.774) and SUB (r g  = 0.778) factors. In our initial decompositions, 33% of total BD variance remained after partialing out SUD and SUB. The majority of covariance between BD and SUB and between BD and SUD was shared across all factors, and, within these models, only a small fraction of the total variation in BD operated via an independent pathway with SUD or SUB outside of the other factor. When only nicotine/tobacco, cannabis, and alcohol were included for the SUB/SUD factors, their correlation increased to r g  = 0.861; in corresponding decompositions, BD-specific variance decreased to 27%. Further research can better elucidate the properties of BD-specific variation by exploring its genetic/molecular correlates., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

South Asia, making up around 25% of the world's population, encompasses a wide range of individuals with tremendous genetic and environmental diversity. This region, which spans eight countries, is home to over 4500 anthropologically defined groups that speak numerous languages and have an array of religious beliefs and cultures, making it one of the most diverse places in the world. Much of the region's rich genetic diversity and structure is the result of a complex combination of population history, migration patterns, and endogamous practices. Despite the overwhelming size and diversity, South Asians have often been underrepresented in genetic research, making up less than 2% of the participants in genetic studies. This has led to a lack of population specific understanding of genetic disease risks. We aim to raise awareness about underlying genetic diversity in this ancestry group, call attention to the lack of representation of the group, and to highlight strategies for future studies in South Asians., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Extremist far-right ideologies, including scientifically inaccurate beliefs about race, are on the rise (Mieriņa and Koroļeva 2015; Youngblood 2020); individuals perpetuating such ideologies occasionally cite genetics research, including behavioral genetics research. This highlights the need for behavioral geneticists to actively confront extremist ideology and promote anti-racism. We emphasize the need for Diversity, Equity and Inclusion (DEI) committees within behavioral genetics institutions. DEI committees can lead to: greater awareness of ways in which behavioral genetics has been misused (historically and currently) to harm minoritized communities, increased discussions on conducting ethical behavioral genetics research, and increased collaboration for conducting more diverse behavioral genetics research. We discuss the activities and goals of the student-driven DEI committee at the Institute for Behavior Genetics (IBG). At the same time, we acknowledge we have a long way to go, both as a committee and as a field. Our committee is still in its early stages; we discuss challenges to increasing DEI in the field and present future goals for both IBG and the behavioral genetics community as we explore the process of implementing DEI work., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The literature on the association between subjective effects (SEs; i.e., how an individual perceives their physiological and psychological reactions to a drug) and substance use disorders (SUDs) is largely limited to community samples. The present study addressed the following aims in a clinical sample: whether SEs predict general versus substance-specific SUD in adolescence and adulthood after controlling for conduct disorder symptoms (CDsymp); whether SEs predict SUDs across drug classes; whether SEs predict change in SUD from adolescence to adulthood; and whether there are racial/ethnic differences in associations., Methods: Longitudinal analyses were conducted using data from a sample of 744 clinical probands recruited from residential and outpatient SUD treatment facilities in CO during adolescence (M age = 16.26) and re-assessed twice in adulthood (M ages = 22.56 and 28.96), approximately seven and twelve years after first assessment. SEs and CDsymp were assessed in adolescence. SUD severity was assessed at adolescence and twice during adulthood., Results: SEs assessed in adolescence robustly predicted general SUD for legal and illegal substances in adolescence and adulthood, whereas CDsymp predicted SUD primarily in adolescence. Higher positive and negative SEs in adolescence were associated with greater SUD severity after controlling for CDsymp, with similar magnitudes. Results indicated cross-substance effects of SEs on SUD. We found no evidence for racial/ethnic differences in associations., Conclusions: We investigated the progression of SUD in a high-risk sample with greater odds of sustained SUD. In contrast to CDsymp, both positive and negative SEs consistently predicted general SUD across substances in adolescence and adulthood., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1-4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction., (© 2022. The Author(s).)

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects., (© 2022. The Author(s).)

Background: Childhood maltreatment (CM), executive functions (EFs), and psychiatric disorders all correlate highly. Changes in EFs during adolescence related to CM present a possible mediating mechanism for the development of psychiatric disorders, yet no study has analyzed this longitudinally while comparing predictive capacity of different CM factor structures. We hypothesized that changes in EFs from adolescence to adulthood would mediate, in part, associations between CM, internalizing disorders (INT), and anti-social personality disorder (ASPD) while different subtypes of CM would differentially predict INT and ASPD., Objective: This study longitudinally examined the mediating effects of EFs on associations between CM, INT, and ASPD while comparing prediction of two CM factor structures., Participants: High-risk subjects selected for drug use in adolescence (N = 658) from mean ages 16 to 23., Methods: A Bayesian structural equation model was deployed to analyze change in EFs as a mediator of the relationship between CM and adult INT and ASPD. CM was measured using two factor structures: a single overall factor and four correlated factors representing CM subtypes., Results: CM significantly predicted INT and ASPD but there was no evidence that the relationship was substantially mediated through EFs. High correlations among subtypes of CM limited the unique predictions of each subtype on INT and ASPD., Conclusion: In this high-risk sample, the collinearity of CM subtypes obscured their predictions of outcome measures supporting the use of one CM factor. EFs did not significantly mediate associations between CM and psychiatric disorders, but further research on these relationships is warranted., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Research on the influence of cannabis use on anthropometrics, cardiovascular and pulmonary function, and other indicators of physical health has reported mixed results. We examined whether cannabis frequency is associated with physical health outcomes phenotypically and after controlling for shared genetic and environmental factors via a longitudinal co-twin control design., Methods: We tested the phenotypic associations of adolescent, young adult, and adult cannabis frequency with adult physical health. Next, we ran multilevel models to test if significant phenotypic associations remained at the between-family and within-twin pair levels. Participants include 677 individual twins (308 twin pairs) aged 25-35., Results: At the phenotypic level, adolescent cannabis use was associated with less adult exercise engagement (b = - 0.846 min, p = .000). Adult cannabis use was associated with a lower resting heart rate (HR; b = - 0.170 bpm, p = .001) and more frequent appetite loss (b = 0.018, p = .000). Only between-family effects were significant for adolescent cannabis use and exercise engagement (b = - 1.147 min, p = .000) and adult cannabis use and appetite loss frequency (b = 0.041, p = .002). The total within-twin (b = - 0.184, p = .014), MZ only (b = - 0.304, p = .003), and between-family effects (b = - 0.164, p = .025) were significant between adult cannabis use and a lower resting HR, which persisted after controlling for familial confounds and other substance use., Conclusions: The associations between cannabis use with exercise engagement and frequency of appetite loss are explained by familial confounding while the association between cannabis use and resting HR was not. These results do not support a causal association between cannabis use once a week and poorer physical health effects among adults aged 25-35., (Published by Elsevier B.V.)

Individual differences in music traits are heritable and correlated with the development of cognitive and communication skills, but little is known about whether diverse modes of music engagement (e.g., playing instruments vs. singing) reflect similar underlying genetic/environmental influences. Moreover, the biological etiology underlying the relationship between musicality and childhood language development is poorly understood. Here we explored genetic and environmental associations between music engagement and verbal ability in the Colorado Adoption/Twin Study of Lifespan behavioral development & cognitive aging (CATSLife). Adolescents ( N = 1,684) completed measures of music engagement and intelligence at approximately age 12 and/or multiple tests of verbal ability at age 16. Structural equation models revealed that instrument engagement was highly heritable (a² = .78), with moderate heritability of singing (a² = .43) and dance engagement (a² = .66). Adolescent self-reported instrument engagement (but not singing or dance engagement) was genetically correlated with age 12 verbal intelligence and still was associated with age 16 verbal ability, even when controlling for age 12 full-scale intelligence, providing evidence for a longitudinal relationship between music engagement and language beyond shared general cognitive processes. Together, these novel findings suggest that shared genetic influences in part accounts for phenotypic associations between music engagement and language, but there may also be some (weak) direct benefits of music engagement on later language abilities. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Aims: To examine whether moderate adolescent cannabis use has neurocognitive effects that are unexplained by familial confounds, which prior family-controlled studies may not have identified., Design: A quasi-experimental, sibling-comparison design was applied to a prospective, observational study of adolescents with moderate cannabis use. Participants were recruited from 2001 to 2006 (mean age = 17 years). A second wave of data was collected from 2008 to 2013 (mean age = 24 years)., Setting: Two US metropolitan communities., Participants: A total of 1192 adolescents from 596 families participated in this study. Participants were primarily male (64%) and racially and ethnically diverse (non-Hispanic white = 45%). A sibling in each family was a clinical proband identified due to delinquent behaviors. Whereas prior family-controlled studies have used samples of primarily infrequent cannabis users (mean = 1-2 days/month), participants here endorsed levels of cannabis use comparable to findings from epidemiological cohort studies (mean = 7-9 days/month)., Measurements: Semi-structured clinical interviews assessed drug use, and a neuropsychological battery assessed cognitive abilities. Covariates included age at assessment, gender and alcohol use., Findings: After correcting for multiple testing, a greater frequency and earlier onset of regular cannabis use were associated with poorer cognitive performance, specifically on tests of verbal memory. Further, after accounting for familial factors shared by siblings and alcohol use, poorer verbal memory performance was still associated with greater life-time frequency of cannabis use at wave 1 [b = -0.007 (-0.002, -0.012), adjusted P = 0.036]; earlier cannabis use at wave 2 [b = -0.12 (-0.05, -0.19), adjusted P = 0.006; b = -0.14 (-0.06, -0.23), adjusted P = 0.006]; and greater frequency of past 6 months use at wave 2 [b = -0.02 (-0.01, -0.03), adjusted P = 0.002; b = -0.02 (-0.01, -0.03), adjusted P = 0.008]., Conclusions: Moderate adolescent cannabis use may have adverse effects on cognitive functioning, specifically verbal memory, that cannot be explained by familial factors., (© 2020 Society for the Study of Addiction.)

Personality variables are associated with educational attainment and socioeconomic outcomes. In this study we incorporated a polygenic score derived from the largest genome-wide association study (GWAS) of educational attainment to date (Lee et al., 2018) into the Interactionist Model of R. D. Conger, Martin, and Masarik (2021) that describes the influence of socioeconomic factors on individual development. The inclusion of a polygenic score predictive of educational attainment (PS-Edu) into this model, and the use of the multigeneration, longitudinal Family Transitions Project (FTP) provide a unique opportunity to investigate genetic and environmental influences on the development of negative personality traits and educational and economic outcomes. The FTP is a three-generation sample. This study utilized data from the first generation (G1; mean age 40 at initiation of the FTP) and second generation (G2; assessed at mean ages 18 and 30). Participants are approximately 50% female, 99% of European ancestry, primarily from lower to middle class SES. PS-Edu was significantly correlated with educational attainment in both generations of the FTP, accounting for 4.1 to 6.7% of the variance. Findings confirm that PS-Edu is a complex genetic index that is correlated with all of the socioeconomic constructs in the model. Results suggest potential gene-environment correlation or common genetic influences underlie associations among parenting investments, negative personality traits, and educational attainment. Genetic variance captured by PS-Edu was mediated substantially through G1 parental investments. Although study limitations warrant cautious interpretation, we demonstrate the promise of including polygenic scores in developmental models to better understand genetic and environmental influences on human development. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The multitude of gambling activities has given rise to heterogeneous ways of analyzing these behaviors and may partially underlie the lack of replication in gambling research. The current study used complementary analyses to investigate the structure, typology and etiology of gambling behaviors in a discovery sample of 2,116 twins (54.86% female; M age  = 24.90) and a replication sample of 619 siblings (30.37% female; M age  = 28.00). Our approach was twofold. First, we used confirmatory factor analyses to investigate the structure across the frequency of eight gambling activities. Second, we used factor mixture models to identify gambling frequency subtypes. We assessed associations with gambling frequency as well as conducted genetically informed analyses to estimate the role of genetic and environmental influences. Across samples, a two-factor model fit the data best, with a Common Gambling factor influencing all activities and a separate factor for Skill Gambling. Our study identified four gambling frequency subtypes, which resembled the typology from the Pathways Model. We found distinct demographic, psychiatric, behavioral and genetic risk profiles for the different gambling factors and subtypes with robust associations observed for male sex, risk-taking, sensation seeking, alcohol dependence and problem gambling. Controlling for shared genetic and environmental influences (via co-twin control modeling), we found that sensation seeking directly increased Common Gambling frequency. In sum, we illustrated the utility of multi-dimensional statistical techniques for disentangling the structure and typology from complex multivariate gambling data., (Published by Elsevier Ltd.)

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.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r g ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r gs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors., (© 2020 Society for the Study of Addiction.)

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder., Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations., Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10 -9 ) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10 -9 ). Cannabis use disorder and cannabis use were genetically correlated (r g 0·50, p=1·50 × 10 -21 ), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia., Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder., Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We integrated genomic and bioinformatic analyses, using data from the largest genome-wide association study of cocaine dependence (CD; n = 6546; 82.37% with CD; 57.39% male) and the largest postmortem gene-expression sample of individuals with cocaine use disorder (CUD; n = 36; 51.35% with CUD; 100% male). Our genome-wide analyses identified one novel gene ( NDUFB9 ) associated with the genetic predisposition to CD in African-Americans. The genetic architecture of CD was similar across ancestries. Individual genes associated with CD demonstrated modest overlap across European-Americans and African-Americans, but the genetic liability for CD converged on many similar tissue types (brain, heart, blood, liver) across ancestries. In a separate sample, we investigated the neuronal gene expression associated with CUD by using RNA sequencing of dorsal-lateral prefrontal cortex neurons. We identified 133 genes differentially expressed between CUD case patients and cocaine-free control subjects, including previously implicated candidates for cocaine use/addiction ( FOSB , ARC , KCNJ9/GIRK3 , NR4A2 , JUNB , and MECP2 ). Differential expression analyses significantly correlated across European-Americans and African-Americans. While genes significantly associated with CD via genome-wide methods were not differentially expressed, two of these genes ( NDUFB9 and C1qL2 ) were part of a robust gene coexpression network associated with CUD involved in neurotransmission (GABA, acetylcholine, serotonin, and dopamine) and drug addiction. We then used a "guilt-by-association" approach to unravel the biological relevance of NDUFB9 and C1qL2 in the context of CD. In sum, our study furthers the understanding of the genetic architecture and molecular neuropathology of human cocaine addiction and provides a framework for translating biological meaning into otherwise obscure genome-wide associations. SIGNIFICANCE STATEMENT Our study further clarifies the genetic and neurobiological contributions to cocaine addiction, provides a rapid approach for generating testable hypotheses for specific candidates identified by genome-wide research, and investigates the cross-ancestral biological contributions to cocaine use disorder/dependence for individuals of European-American and African-American ancestries., (Copyright © 2020 the authors.)

We investigated the genetic and molecular architecture of cocaine dependence (CD) and cocaine use by integrating genome-/transcriptome-wide analyses. To prioritize candidates for follow-up investigation, we also sought to translate gene expression findings across species. Using data from the largest genome-wide association study (GWAS) of CD to date (n = 3176, 74% with CD), we assessed genomic heritability, gene-based associations, and tissue enrichment. We detected a significant single-nucleotide polymorphism heritability of 28% for CD and identified three genes (two loci) underlying this predisposition: the C1qL2 (complement component C1 q like 2), KCTD20 (potassium channel tetramerization domain containing 20), and STK38 (serine/threonine kinase 38) genes. Tissue enrichment analyses indicated robust enrichment in numerous brain regions, including the hippocampus. We used postmortem human hippocampal RNA-sequencing data from previous study (n = 15, seven chronic cocaine users) to follow up genome-wide results and to identify differentially expressed genes/transcripts and gene networks underlying cocaine use. Cross-species analyses utilized hippocampal gene expression from a mouse model of cocaine use. Differentially expressed genes/transcripts in humans were enriched for the genes nominally associated with CD via GWAS (P < 0.05) and for differentially expressed genes in the hippocampus of cocaine-exposed mice. We identified KCTD20 as a central component of a hippocampal gene network strongly associated with human cocaine use, and this gene network was conserved in the mouse hippocampus. We outline a framework to map and translate genome-wide findings onto tissue-specific gene expression, which provided biological insight into cocaine use/dependence., (© 2019 Society for the Study of Addiction.)

The ε4 allele of APOE is a well-established genetic risk factor for cognitive aging and dementia, but its influence on early life cognition is unknown. Consequently, we assessed associations of APOE genotypes with cognitive performance during 7, 12, and 16 year-assessments in our ongoing Colorado Adoption/Twin Study of Lifespan behavioral development (CATSLife). In general, APOE ε4 was associated with lower Verbal, Performance, and Full Scale IQ scores during childhood and adolescence (e.g., Full Scale IQ was lower by 1.91 points per ε4 allele, d = -0.13), with larger effects in females (e.g., average Full Scale IQ scores were 3.41 points lower in females per each ε4 allele vs. 0.33 points lower in males). Thus, these results suggest that deleterious effects of the APOE ε4 allele are manifested before adulthood, especially in females, and support both early origin theories and differential life-course vulnerabilities for later cognitive impairment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Limited evidence suggests that early cannabis use is associated with sleep problems. Research is needed to understand the developmental impact of early regular cannabis use on later adult sleep duration., Methods: In a sample of 1656 adult twins (56% female, Mean age = 25.79yrs), linear mixed effects models were used to analyze the influence of retrospectively assessed age of onset of regular cannabis use on adult sleep duration controlling for sex, depression, and current substance use. Twin analyses provided genetic and environmental variance estimates as well as insights into the association and potential casual relationships between these traits., Results: Earlier age of onset for regular cannabis use was significantly associated with shorter adult sleep duration on both weekdays (β = -0.13, 95% CI = [-0.23, -0.04]) and weekends (β = -0.18, 95% CI = [-0.27, -0.08]). Additive genetics significantly contributed to the onset of regular cannabis use (a 2 = 76%, 95% CI = [68, 85]) and adult weekend sleep duration (a 2  = 20%, 95% CI = [11, 32]). We found evidence of a significant genetic correlation (r A = -0.31, 95% CI = [-0.41, -0.15]) between these two traits and our best fitting model was consistent with early onset of regular cannabis use causing shorter adult weekend sleep duration (β = -0.11, 95% CI = [-0.18, -0.03])., Conclusions: Our results are consistent with the hypothesis that early onset of regular cannabis use may have a negative impact on adult sleep duration., (Copyright © 2019. Published by Elsevier B.V.)

Background: Research indicates that early tobacco initiation increases risk for dependence, but despite this, early initiation is associated with slower transitions to escalated tobacco use. In contrast to these findings, other studies suggest that rapid escalated tobacco use is associated with increased dependence outcomes., Methods: Our sample was comprised of 5668 twins (2834 twin-pairs, mean age: 26.89, s.d = 4.42, 53.67% female, 57.69% monozygotic) from Colorado and Minnesota twin cohorts. We assessed the associations between 1) age of tobacco initiation and the speed of transitions (latency) to tobacco problem use and dependence and the associations between 2) age of initiation and latencies to tobacco problem use and dependence with tobacco dependence symptom severity. To further understand the etiological unfolding of these processes, we conducted univariate twin models and causally informative co-twin control models., Results: After adjustment for covariates, we found that early tobacco initiation was associated with a slower transition from initiation to problem use but a faster transition from problem use to dependence. Additionally, we found that earlier initiation and faster transitions to tobacco problem use and dependence predicted greater tobacco dependence severity within twin pairs (consistent with causal influences). The contribution of shared genetic and environmental factors was also evident for these relationships., Conclusions: Our study further disentangles the role of early initiation with transition times to tobacco problem use and dependence. In addition to common risk factors, we found potential causal roles for early tobacco initiation and rapid escalated tobacco use with increased risk for tobacco dependence severity., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Illness behaviors-or responses to bodily symptoms-predict individuals' recovery and functioning; however, there has been little research on the early life personality antecedents of illness behavior. This study's primary aims were to evaluate (a) childhood temperament traits (i.e., emotionality and sociability) as predictors of adult illness behaviors, independent of objective health; and (b) adult temperament traits for mediation of childhood temperament's associations., Method: Participants included 714 (53% male; 350 adoptive family and 364 control family) children and siblings from the Colorado Adoption Project (CAP; Plomin & DeFries, 1983). Structural regression analyses evaluated paths from childhood temperament to illness behavior (i.e., somatic complaints, sick days, and medication use) at two adulthood assessments (CAP years 21 and 30). Analyses controlled for participant age, sex, family type (adoptive or control), adopted status, parent education/occupation, and middle childhood illnesses, doctor visits, and life events stress., Results: Latent illness behavior factors were established across 2 adulthood assessments. Multilevel path analyses revealed that higher emotionality (fearfulness) in adulthood-but not childhood temperament-predicted higher levels of illness behavior at both assessments. Lastly, lower emotionality-fearfulness partially mediated the effect of higher childhood sociability on adult illness behavior., Conclusions: Results suggest the importance of childhood illness experiences and adult emotionality (fearfulness) in shaping illness behavior in early adulthood. They also suggest a small, protective role of childhood sociability on reduced trait fearfulness in adulthood. These findings broaden our understanding of the prospective links between temperament and illness behavior development, suggesting distinct associations from early life illness experiences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Some of the most widely studied variants in psychiatric genetics include variable number tandem repeat variants (VNTRs) in SLC6A3, DRD4, SLC6A4, and MAOA. While initial findings suggested large effects, their importance with respect to psychiatric phenotypes is the subject of much debate with broadly conflicting results. Despite broad interest, these loci remain absent from the largest available samples, such as the UK Biobank, limiting researchers' ability to test these contentious hypotheses rigorously in large samples. Here, using two independent reference datasets, we report out-of-sample imputation accuracy estimates of >0.96 for all four VNTR variants and one modifying SNP, depending on the reference and target dataset. We describe the imputation procedures of these candidate variants in 486,551 UK Biobank individuals, and have made the imputed variant data available to UK Biobank researchers. This resource, provided to the scientific community, will allow the most rigorous tests to-date of the roles of these variants in behavioral and psychiatric phenotypes.

Human laboratory studies and twin research investigating relationships between alcohol use/pathology and gambling generally have yielded contradictory results, sometimes suggesting causal relationships and common genetic risk factors. 2860 individuals (mean age: 25.60, s.d = 3.21, 50.62% female) from separate clinical (n = 636) and community based (twin) samples (n = 2224) were used to assess associations between past year alcohol use and frequency of past year gambling behaviors (gambling frequency). After adjustment for demographic and psychiatric covariates, individual-level analyses detected that increased alcohol use was associated with more frequent gambling behaviors in twin and clinical samples. Co-twin control models were then used to test potential causal (direct) relationships between alcohol use and gambling frequency. Controlling for all covariates and shared genetic/environmental factors, we found increased alcohol use directly predicted more frequent gambling behaviors (consistent with causality). Our study also suggests shared genetic and/or environmental risk factors contribute to the association between increased alcohol use and frequent gambling behavior, a finding that may be more pronounced in males. The present study helps bridge the gap between twin research and human laboratory studies on gambling and alcohol use and corroborates findings across community and clinical samples. Overall, our findings support both common risk factors between alcohol use and gambling as well as a direct relationship between alcohol use and gambling frequency. Recognizing these dual processes could prove useful for gambling-related prevention/intervention programs., (Published by Elsevier Ltd.)

Background: Studies have shown a correlation between language abilities and alcohol use; however, results are inconsistent. A recent study using a discordant twin design showed an association between early child language development and later alcohol use behaviors; i.e., the twin with more advanced language abilities was more likely to try alcohol earlier in adolescence (Latvala et al., 2014). The authors suggested that this could result from better socialization of individuals with greater language abilities, which could lead to more opportunities for alcohol experimentation. The findings by Latvala et al. raise interesting questions, but the study has limitations, and replication is needed., Method: We aimed to replicate and build upon these results utilizing 488 same sex twin pairs from the Colorado Longitudinal Twin Study, a longitudinal sample with quantitative measures of language abilities starting when the twins were 14 months old., Results: We found no significant correlations between a latent measure of child language abilities or measures of general cognitive ability at ages 14, 20, and 24 months and a latent alcohol use variable at ages 17 and 22 years., Conclusion: Our results did not replicate the association between early language ability and later alcohol use reported by Latvala et al. Possible reasons for differing results across samples, including varying cultural norms as well as differences in educational attainment, peer influences, and novelty seeking, were discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Youth with loss of control eating (LOC) have poorer social relationships than youth without LOC. However, perceived family functioning among youth reporting LOC is relatively unexplored. We examined perceived family functioning among 990 twins (age = 17.47 ± 0.71 years, 53% female) from the Colorado Center for Antisocial Drug Dependence with (n = 158) and without (n = 832) LOC. LOC was assessed with one binary item. Associations between family functioning and LOC were examined using general linear models that accounted for dependence in twin data. Girls with greater family conflict had higher odds of endorsing LOC (p = .02), but not after accounting for depressive symptoms (p = .26). Further analysis indicated that depressive symptoms mediated the association between LOC and family conflict (p = .04). This finding is consistent with an interpersonal model, which proposes that interpersonal difficulties lead to negative emotional states, which promotes LOC as a method of coping with negative affect. Family cohesion and expressiveness were not associated with LOC in girls, and none of the family functioning variables were associated with LOC in boys (ps > .05). Future studies are needed to clarify these relations and to determine any relevant treatment indications., (Copyright © 2019. Published by Elsevier Ltd.)

Exposure to stressful life events increases risk for both internalizing and externalizing psychopathology, but less is known about moderators of the association between stressful life events and psychopathology. The present study examined the influence of stressful life events, psychopathy, and their interaction on internalizing and externalizing psychopathology in 3877 individuals from the community. We hypothesized that (1) exposure to stressful life events would be a transdiagnostic risk factor for psychopathology, (2) primary and secondary psychopathy would be differentially associated with internalizing psychopathology, and (3) primary psychopathy would moderate the association between stressful life events and internalizing psychopathology. Confirming existing findings, our results were consistent with the first and second hypotheses. In contrast to our third hypothesis, primary psychopathy was not associated with stressful life events in childhood, inconsistently associated with stressful life events in adolescence, and did not moderate the association between stressful life events and internalizing psychopathology. Furthermore, stressful life events across development were associated with secondary psychopathy and internalizing and externalizing psychopathology. We also found similar associations between stressful life events, psychopathy, and psychopathology in females and males. Future studies investigating the impact of stressful life events on psychopathology should include psychopathic traits and stress-reactivity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6-11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10 -13 ) and African ancestries (rs2066702; P = 2.2 × 10 -9 ). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Background and Aims: Adolescents with conduct and substance use problems are at increased risk for premature mortality, but the extent to which these risk factors reflect family- or individual-level differences and account for shared or unique variance is unknown. This study examined common and independent contributions to mortality hazard in adolescents ascertained for conduct disorder (CD) and substance use disorder (SUD), their siblings and community controls, hypothesizing that individual differences in CD and SUD severity would explain unique variation in mortality risk beyond that due to clinical/control status and demographic factors., Design: Mortality analysis in a prospective study (Genetics of Antisocial Drug Dependence Study) that began in 1993., Setting: Multi-site sample recruited in San Diego, California and Denver, Colorado, USA., Participants: A total of 1463 clinical probands were recruited through the juvenile correctional system, court-mandated substance abuse treatment programs and correctional schools, along with 1399 of their siblings, and 904 controls., Measurements: Mortality and cause-of-death were assessed via National Death Index search (released October, 2017)., Findings: There were 104 deaths documented among 3766 (1168 female) adolescents and young adults (average age 16.79 years at assessment, 32.69 years at death/censoring). Mortality hazard for clinical probands and their siblings was 4.99 times greater than that of controls (95% confidence interval = 2.40-10.40; P < 0.001). After accounting for demographic characteristics, site, clinical status, familial dependence and shared contributions of CD and SUD, CD independently predicted mortality hazard, whereas SUD severity did not., Conclusions: In the United States, youth with conduct and substance use disorders and their siblings face far greater risk of premature death than demographically similar community controls. In contrast to substance use disorder severity, conduct disorder is a robust predictor of unique variance in all-cause mortality hazard beyond other risk factors., (© 2018 Society for the Study of Addiction.)

Background and Aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants., Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals., Results: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r 2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant., Conclusion: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders., (© 2018 Society for the Study of Addiction.)

Externalizing problems (EP), including rule-breaking, aggression, and criminal involvement, are highly prevalent during adolescence, but the adult outcomes of adolescents exhibiting EP are characterized by heterogeneity. Although many youths' EP subside after adolescence, others' persists into adulthood. Characterizing the development of severe EP is essential to prevention and intervention efforts. Multiple predictors of adult antisocial personality disorder (ASPD) and legal outcomes of a large sample (N = 1205) of clinically- or legally-ascertained adolescents (ages 12-19 years) with severe EP were examined. Many psychosocial predictors hypothesized to predict persistence of EP demonstrated zero-order associations with adult outcomes, but accounted for little unique variation after accounting for baseline conduct disorder symptoms (CD) and demographic factors. Baseline measures of intelligence, which explained independent variation in legal outcomes, provided the only consistent exception to this pattern, though future work is needed to parse these effects from those of socioeconomic factors. CD severity during adolescence is a parsimonious index of liability for persistence of EP into adulthood that explains outcome variance above and beyond all other demographic and psychosocial predictors in this sample., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: The acquired preparedness model (APM) integrates personality trait research and psychosocial learning, which are theorized to ultimately increase risk for problematic substance use outcomes., Methods: The present study uses the APM to examine the potential mediational role of positive and negative expectancies on the relationship between impulsivity and two marijuana outcomes (ie, frequency of use and marijuana use disorder [MUD] symptom count) among an at-risk sample of young adults with history of antisocial behavior and substance use in adolescence and their siblings (n = 312)., Results: Results suggest a significant indirect effect of sensation seeking on recent marijuana use through positive marijuana expectancies. There also was a significant indirect effect of sensation seeking on past-year MUD symptoms through positive expectancies. No significant indirect effects through negative expectancies were found for either outcome., Discussion and Conclusions: Our findings are consistent with the APM and suggest that higher sensation seeking is related to increased positive beliefs about marijuana outcomes, which is related to higher marijuana use and more MUD symptoms., Scientific Significance: These findings suggest that positive expectancies are an important risk factor for marijuana use and misuse, particularly for at-risk individuals with elevated rates of sensation seeking. Positive marijuana expectancies may be important to address in interventions for at-risk individuals. (Am J Addict 2018;XX:1-6)., (© 2018 American Academy of Addiction Psychiatry.)

We investigated the etiological role of genetic and environmental influences for two milestones of tobacco and alcohol use: age of initiation, and speed of progression to dependence (latency). Study participants included 1352 monozygotic and 1422 dizygotic twins (mean age at assessment = 24.31). Earlier ages of initiation significantly increased the likelihood of developing dependence, but were associated with longer dependence latencies for tobacco and alcohol. Latencies to dependence were heritable traits for tobacco (a 2  = 0.63) and alcohol (a 2  = 0.64). Genetic influences contributing to early age of initiation were associated with faster latencies to dependence but sometimes were counteracted by environmental factors, the extent to which depended on substance and, sometimes, sex. Our findings may have important implications for public policy and add to the literature by characterizing the genetic and environmental contributions to the speed of progression to tobacco and alcohol dependence.

Impulsivity is a personality-based risk factor that has been well studied in relation to risky sexual behavior. Recent conceptualizations of impulsivity have proposed multidimensional facets comprised of premeditation, perseverance, sensation seeking, negative urgency, and positive urgency (UPPS-P model). Prior studies have found that these facets are associated with risky sexual behavior in adolescent and college student samples, but no prior studies have evaluated them in clinical samples. The current study examined how impulsivity-related traits related to two different risky sexual behaviors in a clinical sample of at-risk young adults who had both conduct disorder and substance use disorder symptoms as adolescents (n = 529). Lack of premeditation was also tested as a moderator of the relationship between facets of impulsivity and both risky sex outcomes. Results demonstrated that sensation seeking, negative urgency, and positive urgency were correlated with risky sex behaviors. Additionally, multiple regression analyses indicated that sensation seeking was uniquely associated with the number of sexual partners in the past 5 years, whereas positive urgency was uniquely associated with unprotected sex while under the influence. Finally, a significant interaction between lack of premeditation and negative urgency suggests that at-risk young adults with both high negative urgency and lack of premeditation were the likeliest to have the most sexual partners in the past 5 years. This study adds to the current understanding of the relationship between reward- and affect-driven facets of impulsivity and risky sexual behaviors and may lend utility to the development of interventions for at-risk populations.

Risky driving behaviors are disproportionately high among young adults and impulsivity is a robust risk factor. Recent conceptualizations have proposed multidimensional facets of impulsivity comprised of negative urgency, premeditation, perseverance, sensation seeking, and positive urgency (UPPS-P model). Prior studies have found these facets are associated with risky driving behaviors in college student samples, but no prior studies have examined these facets in clinical samples. This study examined the unique and interactive effects of UPPS-P impulsivity facets on past-year risky driving behaviors in a sample of high-risk young adults (ages 18-30 years) with a history of substance use and antisocial behavior and their siblings ( n =1,100). Multilevel Poisson regressions indicated that sensation seeking and negative urgency were uniquely and positively associated with both frequency of past-year reckless driving and driving under the influence. Moreover, lack of premeditation was uniquely and positively associated with reckless driving, whereas lack of perseverance was uniquely and positively associated with driving under the influence. Furthermore, lack of premeditation moderated and strengthened the positive association between sensation seeking and driving under the influence. These study findings suggest that assessing multiple facets of trait impulsivity could facilitate targeted prevention efforts among young adults with a history of externalizing psychopathology.

Poor executive functions (EFs) have been linked to substance use and abuse across multiple substances. However, it is unclear whether these associations are stronger for some EFs over others and/or some stages of substance use over others (e.g., ever using substances vs. dependence). It is also unknown whether such patterns change from adolescence to early adulthood, a transition that is characterized by changes to both EFs and substance use behaviors. In this longitudinal study of approximately 850 twins, we examined the relations between multiple EF abilities (including a common EF factor predicting 9 EF tasks) and measures of general substance use and dependence/abuse in late adolescence (mean age 17 years) and early adulthood (mean age 23 years). At the phenotypic level, common EF in adolescence was negatively related to the number of substances ever used and to last 6-month frequency of use, but not to dependence/abuse vulnerability (i.e., the number of dependence and abuse symptoms endorsed per substance that had been repeatedly used). However, in the same participants in early adulthood, common EF was only weakly related to the number of substances used, and not related to concurrent frequency of use nor dependence/abuse vulnerability. Twin analyses revealed that these associations were primarily genetic in origin, and that the genetic correlations were relatively stable over time. These results suggest that low common EF is a genetic risk factor for increased polysubstance use in late adolescence, but that non-EF factors play a larger role in the progression to substance dependence/abuse. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)