Associations between executive functions assessed in different contexts in a genetically informative sample.

Executive functions (EFs) are cognitive functions that help direct goal-related behavior. EFs are usually measured via behavioral tasks assessed in highly controlled laboratory settings under the supervision of a research assistant. Online versions of EF tasks are an increasingly popular alternative to in-lab testing. However, researchers do not have the same control over the testing environment during online EF assessments. To assess the extent to which EFs assessed in-lab and online are related, we used data from the Colorado Online Twin Study (CoTwins; 887 individual twins aged 13.98-19.05) and constructed an Lab Common EF factor and an Online Common EF factor from four EF tasks assessed in-lab and online. The Lab Common and Online Common EF factors were genetically identical (rA = 1.00) but phenotypically separable (r = .77, 95% confidence interval [0.59, 0.94]) indicating that these EF factors have the same genetic underpinnings but may be differentially influenced by environmental factors. We examined phenotypic, genetic, and environmental correlations between the EF factors and a general cognitive ability factor (g) assessed in the lab and found similar relationships between Lab Common EF and g and Online Common EF and g. Overall, these results suggest that Common EF factors assessed in different contexts are highly related to each other and similarly related to other cognitive outcomes. These findings indicate that online task-based EF assessments could be a viable strategy for increasing sample sizes in large-scale studies, particularly genetically informed studies. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Limited psychological and social effects of lifetime cannabis use frequency: Evidence from a 30-year community study of 4,078 twins.

BACKGROUND: Cannabis use is associated with outcomes like income, legal problems, and psychopathology. This finding rests largely on correlational research designs, which rely at best on statistical controls for confounding. Here, we control for unmeasured confounders using a longitudinal study of twins. METHOD: In a sample of 4,078 American adult twins first assessed decades ago, we used cotwin control mixed effects models to evaluate the effect of lifetime average frequency of cannabis consumption measured on substance use, psychiatric, and psychosocial outcomes. RESULTS: On average, participants had a lifetime cannabis frequency of about one to two times per month, across adolescence and adulthood. As expected, in individual-level analyses, cannabis use was significantly associated with almost all outcomes in the expected directions. However, when comparing each twin to their cotwin, which inherently controls for shared genes and environments, we observed within-pair differences consistent with possible causality in three of the 22 assessed outcomes: cannabis use disorder symptoms (ßW-Pooled = .15, SE = .02, p = 1.7 × 10-22), frequency of tobacco use (ßW-Pooled = .06, SE = .01, p = 1.2 × 10-5), and illicit drug involvement (ßW-Pooled = .06, SE = .02, p = 1.2 × 10-4). Covariate specification curve analyses indicated that within-pair effects on tobacco and illicit drug use, but not cannabis use disorder, attenuated substantially when covarying for lifetime alcohol and tobacco use. CONCLUSIONS: The cotwin control results suggest that more frequent cannabis use causes small increases in cannabis use disorder symptoms, approximately 1.3 symptoms when going from a once-a-year use to daily use. For other outcomes, our results are more consistent with familial confounding, at least in this community population of twins. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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

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

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

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

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

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

Evaluating longitudinal relationships between parental monitoring and substance use in a multi-year, intensive longitudinal study of 670 adolescent twins.

Introduction: Parental monitoring is a key intervention target for adolescent substance use, however this practice is largely supported by causally uninformative cross-sectional or sparse-longitudinal observational research designs. Methods: We therefore evaluated relationships between adolescent substance use (assessed weekly) and parental monitoring (assessed every two months) in 670 adolescent twins for two years. This allowed us to assess how individual-level parental monitoring and substance use trajectories were related and, via the twin design, to quantify genetic and environmental contributions to these relationships. Furthermore, we attempted to devise additional measures of parental monitoring by collecting quasi-continuous GPS locations and calculating a) time spent at home between midnight and 5am and b) time spent at school between 8am-3pm. Results: ACE-decomposed latent growth models found alcohol and cannabis use increased with age while parental monitoring, time at home, and time at school decreased. Baseline alcohol and cannabis use were correlated (r = .65) and associated with baseline parental monitoring (r = -.24 to -.29) but not with baseline GPS measures (r = -.06 to -.16). Longitudinally, changes in substance use and parental monitoring were not significantly correlated. Geospatial measures were largely unrelated to parental monitoring, though changes in cannabis use and time at home were highly correlated (r = -.53 to -.90), with genetic correlations suggesting their relationship was substantially genetically mediated. Due to power constraints, ACE estimates and biometric correlations were imprecisely estimated. Most of the substance use and parental monitoring phenotypes were substantially heritable, but genetic correlations between them were not significantly different from 0. Discussion: Overall, we found developmental changes in each phenotype, baseline correlations between substance use and parental monitoring, co-occurring changes and mutual genetic influences for time at home and cannabis use, and substantial genetic influences on many substance use and parental monitoring phenotypes. However, our geospatial variables were mostly unrelated to parental monitoring, suggesting they poorly measured this construct. Furthermore, though we did not detect evidence of genetic confounding, changes in parental monitoring and substance use were not significantly correlated, suggesting that, at least in community samples of mid-to-late adolescents, the two may not be causally related.

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

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

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

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

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.

The ILHBN: challenges, opportunities, and solutions from harmonizing data under heterogeneous study designs, target populations, and measurement protocols.

The ILHBN is funded by the National Institutes of Health to collaboratively study the interactive dynamics of behavior, health, and the environment using Intensive Longitudinal Data (ILD) to (a) understand and intervene on behavior and health and (b) develop new analytic methods to innovate behavioral theories and interventions. The heterogenous study designs, populations, and measurement protocols adopted by the seven studies within the ILHBN created practical challenges, but also unprecedented opportunities to capitalize on data harmonization to provide comparable views of data from different studies, enhance the quality and utility of expensive and hard-won ILD, and amplify scientific yield. The purpose of this article is to provide a brief report of the challenges, opportunities, and solutions from some of the ILHBN's cross-study data harmonization efforts. We review the process through which harmonization challenges and opportunities motivated the development of tools and collection of metadata within the ILHBN. A variety of strategies have been adopted within the ILHBN to facilitate harmonization of ecological momentary assessment, location, accelerometer, and participant engagement data while preserving theory-driven heterogeneity and data privacy considerations. Several tools have been developed by the ILHBN to resolve challenges in integrating ILD across multiple data streams and time scales both within and across studies. Harmonization of distinct longitudinal measures, measurement tools, and sampling rates across studies is challenging, but also opens up new opportunities to address cross-cutting scientific themes of interest.

Health behavior changes, such as prevention of suicidal thoughts and behaviors, smoking, drug use, and alcohol use; and the promotion of mental health, sleep, and physical activities, and decreases in sedentary behavior, are difficult to sustain. The ILHBN is a cooperative agreement network funded jointly by seven participating units within the National Institutes of Health to collaboratively study how factors that occur in individuals' everyday life and in their natural environment influence the success of positive health behavior changes. This article discusses how information collected using smartphones, wearables, and other devices can provide helpful active and passive reflections of the participants' extent of risk and resources at the moment for an extended period of time. However, successful engagement and retention of participants also require tailored adaptations of study designs, measurement tools, measurement intervals, study span, and device choices that create hurdles in integrating (harmonizing) data from multiple studies. We describe some of the challenges, opportunities, and solutions that emerged from harmonizing intensive longitudinal data under heterogeneous study and participant characteristics within the ILHBN, and share some tools and recommendations to facilitate future data harmonization efforts.

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.

Smoking cessation, harm reduction, and biomarkers protocols in the PhenX Toolkit: Tools for standardized data collection.

The use of standard protocols in studies supports consistent data collection, improves data quality, and facilitates cross-study analyses. Funded by the National Institutes of Health, the PhenX (consensus measures for Phenotypes and eXposures) Toolkit is a catalog of recommended measurement protocols that address a wide range of research topics and are suitable for inclusion in a variety of study designs. In 2020, a PhenX Working Group of smoking cessation experts followed a well-established consensus process to identify and recommend measurement protocols suitable for inclusion in smoking cessation and smoking harm reduction studies. The broader scientific community was invited to review and provide feedback on the preliminary recommendation of the Working Group. Fourteen selected protocols for measuring smoking cessation, harm reduction, and biomarkers research associated with smoking cessation were released in the PhenX Toolkit ( https://www.phenxtoolkit.org) in February 2021. These protocols complement existing PhenX Toolkit content related to tobacco regulatory research, substance use and addiction research, and other measures of smoking-related health outcomes. Adopting well-established protocols enables consistent data collection and facilitates comparing and combining data across studies, potentially increasing the scientific impact of individual studies.

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.

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

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.

Individual differences in adolescent and young adult daily mobility patterns and their relationships to big five personality traits: a behavioral genetic analysis.

Youth behavior changes and their relationships to personality have generally been investigated using self-report studies, which are subject to reporting biases and confounding variables. Supplementing these with objective measures, like GPS location data, and twin-based research designs, which help control for confounding genetic and environmental influences, may allow for more rigorous, causally informative research on adolescent behavior patterns. To investigate this possibility, this study aimed to (1) investigate whether behavior changes during the transition from adolescence to emerging adulthood are evident in changing mobility patterns, (2) estimate the influence of adolescent personality on mobility patterns, and (3) estimate genetic and environmental influences on mobility, personality, and the relationship between them. Twins aged Fourteen to twenty-two (N=709, 55% female) provided a baseline personality measure, the Big Five Inventory, and multiple years of smartphone GPS data from June 2016 - December 2019. Mobility, as measured by daily locations visited and distance travelled, was found via mixed effects models to increase during adolescence before declining slightly in emerging adulthood. Mobility was positively associated with Extraversion and Conscientiousness (r of 0.17 - 0.25, r of 0.10 - 0.16) and negatively with Openness (r of -0.11 - -0.13). ACE models found large genetic (A = 0.56 - 0.81) and small-moderate environmental (C of 0.12 - 0.28, E of 0.07 - 0.15) influences on mobility. A and E influences were highly shared across mobility measures (rg = 0.70, re= 0.58). Associations between mobility and personality were partially explained by mutual genetic influences (rg of -0.27 - 0.53). Results show that as autonomy increases during adolescence and emerging adulthood, we see corresponding increases in youth mobility. Furthermore, the heritability of mobility patterns and their relationship to personality demonstrate that mobility patterns are informative, psychologically meaningful behaviors worthy of continued interest in psychology.

Developmental and etiological patterns of substance use from adolescence to middle age: A longitudinal twin study.

BACKGROUND: The common liability to addiction framework suggests the tendency to use substances is largely a general heritable liability, but little is known about how expression of liability varies across development. We evaluated average developmental trajectories and covariation underlying commonly used substances using a genetically informative prospective design spanning three decades. METHODS: Using a sample of 3762 twins across seven waves of assessment spanning ages 14-40, we modeled these relationships using two complementary approaches: piecewise latent growth and common factor modeling on four measures of alcohol, tobacco, and marijuana use RESULTS: Average use increased across adolescence and either stabilized (alcohol frequency) or declined (all others) in adulthood. Trajectories were heritable (~.35-.75), and genetically correlated with one another (~.40-.80). The random intercepts, centered at age 16, exhibited shared environmental correlations across substances. We found moderate to large phenotypic (rp~.3-.9) and genetic correlations (rg~.3-1) among the longitudinally varying common factors loading on use of each substance at each age. The factor loadings declined with age, reflecting waning influence of common etiology in substance use. CONCLUSIONS: Trajectories of substance use were strongly correlated with each other and influenced primarily by genetic and non-shared environment. A heritable common factor accounted for co-occurring substance use from mid-adolescence to mid-adulthood, and greater substance specificity emerged with maturation. These results extend and reinforce prior work examining consumption and problem use, providing new evidence over a broad age range showing that substance use behaviors are influenced by a more general liability in adolescence and specificity increases across development.

Bayesian Forecasting with a Regime-Switching Zero-Inflated Multilevel Poisson Regression Model: An Application to Adolescent Alcohol Use with Spatial Covariates.

In this paper, we present and evaluate a novel Bayesian regime-switching zero-inflated multilevel Poisson (RS-ZIMLP) regression model for forecasting alcohol use dynamics. The model partitions individuals' data into two phases, known as regimes, with: (1) a zero-inflation regime that is used to accommodate high instances of zeros (non-drinking) and (2) a multilevel Poisson regression regime in which variations in individuals' log-transformed average rates of alcohol use are captured by means of an autoregressive process with exogenous predictors and a person-specific intercept. The times at which individuals are in each regime are unknown, but may be estimated from the data. We assume that the regime indicator follows a first-order Markov process as related to exogenous predictors of interest. The forecast performance of the proposed model was evaluated using a Monte Carlo simulation study and further demonstrated using substance use and spatial covariate data from the Colorado Online Twin Study (CoTwins). Results showed that the proposed model yielded better forecast performance compared to a baseline model which predicted all cases as non-drinking and a reduced ZIMLP model without the RS structure, as indicated by higher AUC (the area under the receiver operating characteristic (ROC) curve) scores, and lower mean absolute errors (MAEs) and root-mean-square errors (RMSEs). The improvements in forecast performance were even more pronounced when we limited the comparisons to participants who showed at least one instance of transition to drinking.

Genetic correlation, pleiotropy, and causal associations between substance use and psychiatric disorder.

BACKGROUND: Substance use occurs at a high rate in persons with a psychiatric disorder. Genetically informative studies have the potential to elucidate the etiology of these phenomena. Recent developments in genome-wide association studies (GWAS) allow new avenues of investigation. METHOD: Using results of GWAS meta-analyses, we performed a factor analysis of the genetic correlation structure, a genome-wide search of shared loci, and causally informative tests for six substance use phenotypes (four smoking, one alcohol, and one cannabis use) and five psychiatric disorders (ADHD, anorexia, depression, bipolar disorder, and schizophrenia). RESULTS: Two correlated externalizing and internalizing/psychosis factor were found, although model fit was beneath conventional standards. Of 458 loci reported in previous univariate GWAS of substance use and psychiatric disorders, about 50% (230 loci) were pleiotropic with additional 111 pleiotropic loci not reported from past GWAS. Of the 341 pleiotropic loci, 152 were associated with both substance use and psychiatric disorders, implicating neurodevelopment, cell morphogenesis, biological adhesion pathways, and enrichment in 13 different brain tissues. Seventy-five and 114 pleiotropic loci were specific to either psychiatric disorders or substance use phenotypes, implicating neuronal signaling pathway and clathrin-binding functions/structures, respectively. No consistent evidence for phenotypic causation was found across different Mendelian randomization methods. CONCLUSIONS: Genetic etiology of substance use and psychiatric disorders is highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking. In aggregate, the patterns are not consistent with vertical pleiotropy, more likely reflecting horizontal pleiotropy or more complex forms of phenotypic causation.