Genetic diversity fuels gene discovery for tobacco and alcohol use.

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 injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. 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.

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.

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

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

Longitudinal effects and environmental moderation of ALDH2 and ADH1B gene variants on substance use from age 14 to 40.

Alcohol use and dependence are strongly affected by variation in aldehyde dehydrogenase (ALDH2) and, to a lesser extent, alcohol dehydrogenase (ADH1B) genes. We use this genetic variation with an adoption design to test the causal role of alcohol use on other drug use, as well as the moderating role of adoptive parent, sibling, and peer alcohol use. Longitudinal models were run on 412 genotyped adopted individuals of East Asian ancestry with multiple assessments between ages 14 and 40. We found robust associations between alcohol frequency, quantity, and maximum drinks and ALDH2, but not ADH1B, status. The magnitude of the ALDH2 protective effect increased with age, particularly for maximum drinks, though estimates were smaller than previously reported in ancestrally similar individuals in East/North-East Asian countries. These results suggest that sociocultural factors in Minnesota may reduce the protective effects of ALDH2. We found that peer alcohol use, but not parent or sibling use, predicted adopted offspring's use, and that these environmental influences did not vary by ALDH2 status. Finally, we did not find strong evidence of associations between ALDH2 status and tobacco, marijuana, or illegal drug use, contrary to expectation if alcohol serves as a gateway to use of other drugs.

The role of the shared environment in college attainment: An adoption study.

OBJECTIVE: College attainment is one of the few phenotypes to have substantial variance accounted for by environmental factors shared by reared-together relatives. The shared environment is implicated by the consistently strong parent-to-offspring transmission of college attainment. The mechanisms underlying this relationship remain unclear. We use genetically informative methods with a longitudinal, adoption sample to identify possible environmental mechanisms underlying parent-offspring college transmission. METHOD: Data were drawn from the Sibling Interaction and Behavior Study (SIBS), which includes 409 adoptive and 208 nonadoptive families, consisting of two offspring followed from adolescence into young adulthood and their rearing parents. Four domains of environmental mechanisms were examined: (a) skill enhancement; (b) academic support; (c) material advantage; and (d) supportive family environment. RESULTS: Both shared environmental and genetic factors contributed to the parent-offspring transmission of college attainment. However, highly educated parents did not appear to be increasing their adopted offspring's attainment through skill development. The environmental factors that were associated with increased odds of offspring college attainment were mother's academic expectations and family income. CONCLUSIONS: While complete mediation of the parent-offspring transmission of college attainment was not identified, the results shed light on some of the mechanisms associated with the common environment variance in the college attainment phenotype.

Sibling Comparison Designs: Addressing Confounding Bias with Inclusion of Measured Confounders.

Genetically informative research designs are becoming increasingly popular as a way to strengthen causal inference with their ability to control for genetic and shared environmental confounding. Co-twin control (CTC) models, a special case of these designs using twin samples, decompose the overall effect of exposure on outcome into a within- and between-twin-pair term. Ideally, the within-twin-pair term would serve as an estimate of the exposure effect controlling for genetic and shared environmental factors, but it is often confounded by factors not shared within a twin-pair. Previous simulation work has shown that if twins are less similar on an unmeasured confounder than they are on an exposure, the within-twin-pair estimate will be a biased estimate of the exposure effect, even more biased than the individual, unpaired estimate. The current study uses simulation and analytical derivations to show that while incorporating a covariate related to the nonshared confounder in CTC models always reduces bias in the within-pair estimate, it will be less biased than the individual estimate only in a narrow set of circumstances. The best case for bias reduction in the within-pair estimate occurs when the within-twin-pair correlation in exposure is less than the correlation in the confounder and the twin-pair correlation in the covariate is high. Additionally, the form of covariate inclusion is compared between adjustment for only one's own covariate value and adjustment for the deviation of one's own value from the covariate twin-pair mean. Results show that adjusting for the deviation from the twin-pair mean results in equal or reduced bias.

Mediating pathways from childhood ADHD to adolescent tobacco and marijuana problems: roles of peer impairment, internalizing, adolescent ADHD symptoms, and gender.

BACKGROUND: We examined whether increased risk for adolescent tobacco and marijuana problems associated with childhood ADHD is explained by key intermediary influences during adolescence and differs by gender. METHODS: Longitudinal structural equation models examined mediating effects on problems with both substances (or each substance separately) through age-14 peer impairment, internalizing, and adolescent ADHD symptoms in two twin samples, prospectively assessed since age 11 (N = 2,164). Whether these mediators contributed beyond mediating effects of early-adolescent substance use was also considered. Twin difference analyses further illuminated which mediators might be potentially causal. RESULTS: Direct effects of childhood ADHD on age-17 tobacco and marijuana problems (i.e., independent of included mediators) as well as effects of adolescent ADHD symptoms were significant only for females. By contrast, mediation by peer impairment, evident particularly for marijuana, was relatively stronger for males than females. Depression and anxiety were not prospectively associated with age-17 substance problems when earlier substance problems were considered. Consistent with causal influence of early substance use on later problems, monozygotic twins with more severe tobacco or marijuana problems at age 14 than their co-twins were also more likely to have substance problems later in adolescence. CONCLUSIONS: Mediation through peer impairment, continued presence of ADHD symptoms, and early substance use may alter development so that childhood ADHD indirectly contributes to problems with tobacco and marijuana. Targeting gender-sensitive interventions prior to mid-adolescence, before these patterns become established, is essential.

Genomic Insights for Personalized Care: Motivating At-Risk Individuals Toward Evidence-Based Health Practices.

Background: Lung cancer and tobacco use pose significant global health challenges, necessitating a comprehensive translational roadmap for improved prevention strategies. Polygenic risk scores (PRSs) are powerful tools for patient risk stratification but have not yet been widely used in primary care for lung cancer, particularly in diverse patient populations. Methods: We propose the GREAT care paradigm, which employs PRSs to stratify disease risk and personalize interventions. We developed PRSs using large-scale multi-ancestry genome-wide association studies and standardized PRS distributions across all ancestries. We applied our PRSs to 796 individuals from the GISC Trial, 350,154 from UK Biobank (UKBB), and 210,826 from All of Us Research Program (AoU), totaling 561,776 individuals of diverse ancestry. Results: Significant odds ratios (ORs) for lung cancer and difficulty quitting smoking were observed in both UKBB and AoU. For lung cancer, the ORs for individuals in the highest risk group (top 20% versus bottom 20%) were 1.85 (95% CI: 1.58 - 2.18) in UKBB and 2.39 (95% CI: 1.93 - 2.97) in AoU. For difficulty quitting smoking, the ORs (top 33% versus bottom 33%) were 1.36 (95% CI: 1.32 - 1.41) in UKBB and 1.32 (95% CI: 1.28 - 1.36) in AoU. Conclusion: Our PRS-based intervention model leverages large-scale genetic data for robust risk assessment across populations. This model will be evaluated in two cluster-randomized clinical trials aimed at motivating health behavior changes in high-risk patients of diverse ancestry. This pioneering approach integrates genomic insights into primary care, promising improved outcomes in cancer prevention and tobacco treatment.

Genetic and neural bases of the neuroticism general factor.

We applied structural equation modeling to conduct a genome-wide association study (GWAS) of the general factor measured by a neuroticism questionnaire administered to ∼380,000 participants in the UK Biobank. We categorized significant genetic variants as acting either through the neuroticism general factor, through other factors measured by the questionnaire, or through paths independent of any factor. Regardless of this categorization, however, significant variants tended to show concordant associations with all items. Bioinformatic analysis showed that the variants associated with the neuroticism general factor disproportionately lie near or within genes expressed in the brain. Enriched gene sets pointed to an underlying biological basis associated with brain development, synaptic function, and behaviors in mice indicative of fear and anxiety. Psychologists have long asked whether psychometric common factors are merely a convenient summary of correlated variables or reflect coherent causal entities with a partial biological basis, and our results provide some support for the latter interpretation. Further research is needed to determine the extent to which causes resembling common factors operate alongside other mechanisms to generate the correlational structure of personality.

Impacts of recreational cannabis legalization on cannabis use: a longitudinal discordant twin study.

AIMS: To estimate the effect of recreational legalization on cannabis use frequency and sources of variance across legal environments. DESIGN: Longitudinal discordant twin and gene-environment interaction models in twins recruited from birth records and assessed prospectively. SETTING: The United States, including states with different recreational cannabis policies before and after 2014, when recreational cannabis was first legalized. PARTICIPANTS: Two longitudinal, prospectively assessed samples of American twins aged 24-47 (n = 1425 in legal states, n = 1996 in illegal states), including 111 monozygotic pairs discordant for residence. MEASUREMENTS: Current cannabis use frequency (measured continuously and ordinally) was the primary outcome, and the predictor was recreational status of cannabis (legal/illegal) in the participant's state of residence at the time of assessment. Covariates include age, sex and cannabis use frequency prior to 2014. FINDINGS: Accounting for pre-2014 use, residents of legal states used cannabis more frequently than residents of illegal states (b = 0.21, P = 8.08 × 10-5 ). Comparing 111 pairs of monozygotic twins discordant for residence confirmed the effect (b = 0.18, P = 0.014). There was inconclusive evidence for genetic influences on cannabis use frequency that were specific to the legal environment [χ2  = 2.9 × 10-9 , degrees of freedom (d.f.) = 1, P > 0.999]. Existing genetic influences were moderated by the legal environment, as the genetic correlation between marijuana use before and after legalization was lower in states that legalized (rgenetic  = 0.24) compared with states that did not (rgenetic  = 0.78, Pdifference  = 0.016). CONCLUSIONS: In the United States, there appears to be a ~ 20% average increase in cannabis use frequency attributable to recreational legalization, consistent across increasingly rigorous designs. In addition, the heritability of cannabis use frequency appears to be moderated by legalization.

Mechanisms of parent-child transmission of tobacco and alcohol use with polygenic risk scores: Evidence for a genetic nurture effect.

Parent-child similarity is a function of genetic and environmental transmission. In addition, genetic effects not transmitted to offspring may drive parental behavior, thereby affecting the rearing environment of the child. Measuring genetic proclivity directly, through polygenic risk scores (PRSs), provides a way to test for the effect of nontransmitted parental genotype, on offspring outcome, termed a genetic nurture effect-in other words, if and how parental genomes might affect their children through the environment. The current study used polygenic risk scores for smoking initiation, cigarettes per day, and drinks per week to predict substance use in a sample of 3,008 twins, assessed prospectively from age 17-29, and their parents, from the Minnesota Center for Twin and Family Research. Mixed-effects models were used to test for a genetic nurture effect whereby parental PRSs predict offspring tobacco and alcohol use after statistically adjusting for offspring's own PRS. Parental smoking initiation PRS predicted offspring cigarettes per day at age 24 (ß = .103, 95% CI [.03, .17]) and alcohol use at age 17 (ß = .091, 95% CI [.04, .14]) independent of shared genetics. There was also a suggestive independent association between the parent PRS and offspring smoking at age 17 (ß = .096; 95% CI [.02, .17]). Mediation analyses provided some evidence for environmental effects of parental smoking, alcohol use, and family socioeconomic status. These findings, and more broadly the molecular genetic method used, have implications on the identification of environmental effects on developmental outcomes such as substance use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Where Do Gambling Problems Fit in the Structure of Psychopathology During Emerging Adulthood?

Research suggests major mental disorders co-occur at higher than chance levels. In adult samples, a two factor structure emerges when modeling the higher order structure of psychopathology. Specifically, disorders tend to co-aggregate into two dimensions: Internalizing (depression and anxiety) and Externalizing (acting out, impulsive, and addictive) disorders. Despite this large body of evidence, few studies have integrated problem gambling into this overall model. We used confirmatory factor analysis to model how the symptom count of gambling fits into the structure of psychopathology in a large, community based young adult twin sample of men and women (age 24; N=1329). Twins were assessed via in-person, structured diagnostic interviews on disorders including: Major Depression, Phobias, Post-Traumatic Stress Disorder and Anxiety Disorders (internalizing) and Substance Use Disorders, Gambling Problems (self-report), and Antisocial Behaviors (externalizing). The data were fit to a two-factor structure, with gambling symptoms loading most highly on externalizing, rather than internalizing. The problem gambling loadings did not differ by sex. Implications of these findings suggest that during emerging adulthood gambling problems are best classified and conceptualized in the realm of externalizing disorders for both males and females. Results also suggest prevention and intervention efforts be aimed at young adults who exhibit commonly co-occurring psychopathology.

Differential implications of persistent, remitted, and late-onset ADHD symptoms for substance abuse in women and men: A twin study from ages 11 to 24.

BACKGROUND: Persistence and emergence of ADHD in adulthood are associated with substance problems. We investigate differential implications of ADHD course for tobacco, alcohol, or marijuana problems by sex, then whether substance misuse results from ADHD or contributes to it, through a twin differences design. METHODS: A population-based cohort of 998 twins (61 % monozygotic; 52 % female), born in Minnesota from 1988 to 1994, was prospectively assessed from ages 11-24. Childhood ADHD was oversampled. At age 24, 255 had a history of childhood-onset ADHD (160 persistent, 95 remitted); 93 had late-onset ADHD symptoms identified in late-adolescence/adulthood. Persistent, remitted, and late-onset groups were compared to those without ADHD (N = 459) on childhood characteristics and age-24 substance problems. RESULTS: Persistent and late-onset groups differed in childhood; twin concordances suggested greater genetic etiology for persistent ADHD. As adolescents, however, both groups were high in conduct problems; by adulthood, they were comparably high in substance problems. In particular, women whose ADHD persisted were 5 times more likely to develop tobacco use disorder than women without ADHD. Remitted ADHD was associated with less-increased risk, except for alcohol problems among women. Consistent with possible causality, monozygotic female twins with more age-17 ADHD symptoms than co-twins had more age-24 tobacco symptoms; a similar association was found for alcohol. CONCLUSIONS: Presence or emergence of ADHD in early adulthood increases substance problems to a greater degree for women than men. While effects of substances on later ADHD were not statistically significant, detection was limited by the relative rarity of late-adolescent substance symptoms.

The relationship between subjective well-being and mortality within discordant twin pairs from two independent samples.

Prior research has shown robust associations between greater subjective well-being (SWB) and reduced mortality. Whether this observed association is causal in nature or due instead to confounding genetic or environmental factors affecting both SWB and mortality is not well understood. We used a combined sample of 6,802 twins drawn from two cohorts: the Longitudinal Study of Middle-Aged Danish Twins (MADT; N = 2,815, baseline age between 45 and 69 years, M = 56.8, SD = 6.4) and the Longitudinal Study of Aging Danish Twins (LSADT; N = 3,987, baseline age between 70 and 97 years, M = 76.6, SD = 4.9). The relationship between SWB, encompassing measures of life satisfaction and affect, and all-cause mortality was evaluated using survival analyses at both the individual level and within twin pairs. Twin difference analyses were completed within 1,053 monozygotic (MZ) twin pairs and 1,143 dizygotic (DZ) twin pairs to control for genetic and shared environmental confounding. As expected, the individual-level results showed that higher levels of SWB were associated with reduced mortality: affect hazard ratio (HR) = .90, 95% confidence interval (CI) [.87, .94]; life satisfaction HR = .88, 95% CI [.84, .92]. The effect of SWB on reduced mortality remained significant within both MZ and DZ pairs, suggesting that the association is independent of genetic and nonshared environmental confounding factors. These findings, which generalized across both younger (MADT) and older (LSADT) cohorts of adults, remained significant when accounting for demographic factors, physical health, and cognitive functioning. (PsycINFO Database Record

Associations between childhood ADHD, gender, and adolescent alcohol and marijuana involvement: A causally informative design.

BACKGROUND: We report whether the etiology underlying associations of childhood ADHD with adolescent alcohol and marijuana involvement is consistent with causal relationships or shared predispositions, and whether it differs by gender. METHODS: In three population-based twin samples (N = 3762; 64% monozygotic), including one oversampling females with ADHD, regressions were conducted with childhood inattentive or hyperactive-impulsive symptoms predicting alcohol and marijuana outcomes by age 17. To determine whether ADHD effects were consistent with causality, twin difference analyses divided effects into those shared between twins in the pair and those differing within pairs. RESULTS: Adolescents with more severe childhood ADHD were more likely to initiate alcohol and marijuana use earlier, escalate to frequent or heavy use, and develop symptoms. While risks were similar across genders, females with more hyperactivity-impulsivity had higher alcohol consumption and progressed further toward daily marijuana use than did males. Monozygotic twins with more severe ADHD than their co-twins did not differ significantly on alcohol or marijuana outcomes, however, suggesting a non-causal relationship. When co-occurring use of other substances and conduct/oppositional defiant disorders were considered, hyperactivity-impulsivity remained significantly associated with both substances, as did inattention with marijuana, but not alcohol. CONCLUSIONS: Childhood ADHD predicts when alcohol and marijuana use are initiated and how quickly use escalates. Shared familial environment and genetics, rather than causal influences, primarily account for these associations. Stronger relationships between hyperactivity-impulsivity and heavy drinking/frequent marijuana use among adolescent females than males, as well as the greater salience of inattention for marijuana, merit further investigation.

Increased Risk of Smoking in Female Adolescents Who Had Childhood ADHD.

OBJECTIVE: This study examined the effects of childhood attention deficit hyperactivity disorder (ADHD) symptoms, both inattention and hyperactivity-impulsivity, on the development of smoking in male and female adolescents. METHOD: Twin difference methods were used to control for shared genetic and environmental confounders in three population-based, same-sex twin samples (N=3,762; 64% monozygotic). One cohort oversampled female adolescents with ADHD beginning in childhood. Regressions of childhood inattentive and hyperactive-impulsive symptoms were conducted to predict smoking outcomes by age 17. ADHD effects were divided into those shared between twins in the pair and those nonshared, or different within pairs. RESULTS: Adolescents who had more severe ADHD symptoms as children were more likely to initiate smoking and to start smoking younger. The association of ADHD symptoms with daily smoking, number of cigarettes per day, and nicotine dependence was greater in females than in males. Monozygotic female twins with greater attentional problems than their co-twins had greater nicotine involvement, consistent with possible causal influence. These effects remained when co-occurring externalizing behaviors and stimulant medication were considered. Hyperactivity-impulsivity, while also more strongly related to smoking for female adolescents, appeared primarily noncausal. CONCLUSIONS: Smoking initiation and escalation are affected differentially by ADHD subtype and gender. The association of inattention with smoking in female adolescents may be causal, whereas hyperactivity-impulsivity appears to act indirectly, through shared propensities for both ADHD and smoking.

Parent-Offspring Resemblance for Drinking Behaviors in a Longitudinal Twin Sample.

OBJECTIVE: The purpose of the current study was to evaluate parent-offspring resemblance for alcohol consumption and dependence symptoms, including sex-specific effects, and how these patterns change across adolescence and early adulthood. METHOD: Three cohorts of twins were assessed longitudinally at five time points between ages 14 and 29 years, with parents directly assessed at intake, using structured interviews. Twin offspring and parents from the population-based Minnesota Twin Family Study were included for a total sample size of 3,762 offspring (52% female) and their parents. Alcohol use was measured using an index based on drinking quantity, frequency, maximum drinks, and number of intoxications. Alcohol dependence symptom counts were also used. RESULTS: Parent-offspring correlations for alcohol consumption increased from age 14 (r = .12) to age 17 (r = .25), remained stable from ages 17 through 24, and then decreased slightly by age 29 (r = .19). Familial resemblance for symptoms of alcohol dependence peaked at age 17 (r = .18) then decreased through age 29 (r = .11). Parent-offspring correlations of both measures did not vary significantly by sex of offspring or sex of parent. CONCLUSIONS: Overall, parent-offspring resemblance for alcohol use and problems is relatively stable after early adulthood, with resemblance for alcohol use at higher magnitudes across offspring development. Evidence for differential resemblance based on sex of offspring or parents was lacking.