Designing and Validating a Novel Method for Assessing Delay Discounting Associated With Health Behaviors: Ecological Momentary Assessment Study.

BACKGROUND: Delay discounting quantifies an individual's preference for smaller, short-term rewards over larger, long-term rewards and represents a transdiagnostic factor associated with numerous adverse health outcomes. Rather than a fixed trait, delay discounting may vary over time and place, influenced by individual and contextual factors. Continuous, real-time measurement could inform adaptive interventions for various health conditions. OBJECTIVE: The goals of this paper are 2-fold. First, we present and validate a novel, short, ecological momentary assessment (EMA)-based delay discounting scale we developed. Second, we assess this tool's ability to reproduce known associations between delay discounting and health behaviors (ie, substance use and craving) using a convenience-based sample. METHODS: Participants (N=97) were adults (age range 18-71 years), recruited on social media. In phase 1, data were collected on participant sociodemographic characteristics, and delay discounting was evaluated via the traditional Monetary Choice Questionnaire (MCQ) and our novel method (ie, 7-item time-selection and 7-item monetary-selection scales). During phase 2 (approximately 6 months later), participants completed the MCQ, our novel delay discounting measures, and health outcomes questions. The correlations between our method and the traditional MCQ within and across phases were examined. For scale reduction, a random number of items were iteratively selected, and the correlation between the full and random scales was assessed. We then examined the association between our time- and monetary-selection scales assessed during phase 2 and the percentage of assessments that participants endorsed using or craving alcohol, tobacco, or cannabis. RESULTS: In total, 6 of the 7 individual time-selection items were highly correlated with the full scale (r>0.89). Both time-selection (r=0.71; P<.001) and monetary-selection (r=0.66; P<.001) delay discounting rates had high test-retest reliability across phases 1 and 2. Phase 1 MCQ delay discounting function highly correlated with phase 1 (r=0.76; P<.001) and phase 2 (r=0.45; P<.001) time-selection delay discounting scales. One or more randomly chosen time-selection items were highly correlated with the full scale (r>0.94). Greater delay discounting measured via the time-selection measure (adjusted mean difference=5.89, 95% CI 1.99-9.79), but not the monetary-selection scale (adjusted mean difference=-0.62, 95% CI -3.57 to 2.32), was associated with more past-hour tobacco use endorsement in follow-up surveys. CONCLUSIONS: This study evaluated a novel EMA-based scale's ability to validly and reliably assess delay discounting. By measuring delay discounting with fewer items and in situ via EMA in natural environments, researchers may be better able to identify individuals at risk for poor health outcomes.

Sleep Duration Polygenic Risk and Phenotype: Associations with Biomarkers of Accelerated Aging in the Baltimore Longitudinal Study of Aging.

We sought to explore whether genetic risk for, and self-reported, short sleep are associated with biological aging and whether age and sex moderate these associations. Participants were a subset of individuals from the Baltimore Longitudinal Study of Aging who had complete data on self-reported sleep (n = 567) or genotype (n = 367). Outcomes included: Intrinsic Horvath age, Hannum age, PhenoAge, GrimAge, and DNAm-based estimates of plasminogen activator inhibitor-1 (PAI-1) and granulocyte count. Results demonstrated that polygenic risk for short sleep was positively associated with granulocyte count; compared to those reporting <6 hr sleep, those reporting >7 hr demonstrated faster PhenoAge and GrimAge acceleration and higher estimated PAI-1. Polygenic risk for short sleep and self-reported sleep duration interacted with age and sex in their associations with some of the outcomes. Findings highlight that polygenic risk for short sleep and self-reported long sleep is associated with variation in the epigenetic landscape and subsequently aging.

Identifying novel gene dysregulation associated with opioid overdose death: A meta-analysis of differential gene expression in human prefrontal cortex.

Only recently have human postmortem brain studies of differential gene expression (DGE) associated with opioid overdose death (OOD) been published; sample sizes from these studies have been modest (N = 40-153). To increase statistical power to identify OOD-associated genes, we leveraged human prefrontal cortex RNAseq data from four independent OOD studies and conducted a transcriptome-wide DGE meta-analysis (N = 285). Using a unified gene expression data processing and analysis framework across studies, we meta-analyzed 20 098 genes and found 335 significant differentially expressed genes (DEGs) by OOD status (false discovery rate < 0.05). Of these, 66 DEGs were among the list of 303 genes reported as OOD-associated in prior prefrontal cortex molecular studies, including genes/gene families (e.g., OPRK1, NPAS4, DUSP, EGR). The remaining 269 DEGs were not previously reported (e.g., NR4A2, SYT1, HCRTR2, BDNF). There was little evidence of genetic drivers for the observed differences in gene expression between opioid addiction cases and controls. Enrichment analyses for the DEGs across molecular pathway and biological process databases highlight an interconnected set of genes and pathways from orexin and tyrosine kinase receptors through MEK/ERK/MAPK signaling to affect neuronal plasticity.

Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment.

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five-day within-subject, double-blind, placebo-controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3-5) and completed self-reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post-dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing.

Systematic Review and Meta-analysis of the Relationship Between Exposure to Parental Substance Use and Attention-Deficit/Hyperactivity Disorder in Children.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by persistent patterns of inattention, hyperactivity, and impulsiveness. Among US children and adolescents aged 3-17 years, 9.4% have a diagnosis of ADHD. Previous research suggests possible links between parental substance use and ADHD among children. We conducted a systematic review and meta-analysis of 86 longitudinal or retrospective studies of prenatal or postnatal alcohol, tobacco, or other parental substance use and substance use disorders and childhood ADHD and its related behavioral dimensions of inattention and hyperactivity-impulsivity. Meta-analyses were grouped by drug class and pre- and postnatal periods with combined sample sizes ranging from 789 to 135,732. Prenatal exposure to alcohol or tobacco and parent substance use disorders were consistently and significantly associated with ADHD among children. Other parental drug use exposures resulted in inconsistent or non-significant findings. Prevention and treatment of parental substance use may have potential for impacts on childhood ADHD.

Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.

Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWAS) of smoking behaviors have identified hundreds of significant loci. Most GWAS-identified variants are noncoding with unknown neurobiological effects. We used genome-wide genotype, DNA methylation, and RNA sequencing data in postmortem human nucleus accumbens (NAc) to identify cis-methylation/expression quantitative trait loci (meQTLs/eQTLs), investigate variant-by-cigarette smoking interactions across the genome, and overlay QTL evidence at smoking GWAS-identified loci to evaluate their regulatory potential. Active smokers (N=52) and nonsmokers (N=171) were defined based on cotinine biomarker levels and next-of-kin reporting. We simultaneously tested variant and variant-by-smoking interaction effects on methylation and expression, separately, adjusting for biological and technical covariates and using a two-stage multiple testing approach with eigenMT and Bonferroni corrections. We found >2 million significant meQTL variants (padj<0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects; five meQTLs, mapping to NUDT12, FAM53B, RNF39, and ADRA1B, showed a significant interaction with smoking. We found 57,683 significant eQTLs for 958 unique eGenes (padj<0.05) and no smoking interactions. Colocalization analyses identified loci with smoking-associated GWAS variants that overlapped meQTLs/eQTLs, suggesting that these heritable factors may influence smoking behaviors through functional effects on methylation/expression. One locus containing MUSTIN1 and ITIH4 colocalized across all data types (GWAS + meQTL + eQTL). In this first genome-wide meQTL map in the human NAc, the enriched overlap with smoking GWAS-identified genetic loci provides evidence that gene regulation in the brain helps explain the neurobiology of smoking behaviors.

Association of common infections with cognitive performance in the Baltimore Epidemiologic Catchment Area study follow-up.

INTRODUCTION: Growing evidence suggests that some common infections are causally associated with cognitive impairment; however, less is known about the burden of multiple infections. METHODS: We investigated the cross-sectional association of positive antibody tests for herpes simplex virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and Toxoplasma gondii (TOX) with Mini-Mental State Examination (MMSE) and delayed verbal recall performance in 575 adults aged 41-97 from the Baltimore Epidemiologic Catchment Area Study. RESULTS: In multivariable-adjusted zero-inflated Poisson (ZIP) regression models, positive antibody tests for CMV (p = .011) and herpes simplex virus (p = .018) were individually associated with poorer MMSE performance (p = .011). A greater number of positive antibody tests among the five tested was associated with worse MMSE performance (p = .001). DISCUSSION: CMV, herpes simplex virus, and the global burden of multiple common infections were independently associated with poorer cognitive performance. Additional research that investigates whether the global burden of infection predicts cognitive decline and Alzheimer's disease biomarker changes is needed to confirm these findings.

Longitudinal associations between age 20 problematic substance use and opioid use disorder incidence at age 30 - findings from an urban cohort.

This study used data from a longitudinal prevention study in an urban cohort to examine associations between nicotine dependence, alcohol, and cannabis use disorder and disorder criteria at age 20, with opioid use disorder (OUD) incidence or criteria onset by age 30. The study sample included 1408 participants (57.5% female, 72.5% African American) drawn from two cohorts of participants in a mid-Atlantic region of the U.S. as part of a series of randomized controlled trials of elementary school-based universal prevention interventions. Lifetime cannabis use disorder (CUD), alcohol use disorder (AUD; both DSM-IV), and current nicotine dependence (Fagerstrom Test for Nicotine Dependence, FTND) assessed at age 20 were used to predict (1) DSM-IV lifetime OUD at age 30, and (2) OUD criteria between ages 20 and 30 in multivariable logistic regression models. Covariates for all analyses included sociodemographics (sex, race, and free/reduced-priced lunch status), community disadvantage, and intervention status. Nicotine dependence (FTND≥3) at age 20 predicted age 30 DSM-IV lifetime OUD (aOR = 2.37; 95% CI 1.02,5.54). The number of CUD criteria (aOR = 1.30; 95% CI 1.09,1.57) and nicotine dependence severity scores (aOR = 1.22; 95% CI = 1.05,1.41) at age 20 predicted any OUD criteria between the ages of 20 and 30. Findings are consistent with previous research on opioid use behavior in young adulthood and suggest that nicotine dependence and CUD criteria among urban young people predict onset of OUD and OUD criteria in young adulthood.

Correlates and consequences of anxiety and depressive symptom trajectories during early treatment for alcohol use.

We investigated whether latent trajectories of anxiety and depressive symptoms were associated with clinically relevant variables including treatment attrition among individuals seeking treatment for alcohol use. Participants were drawn from 78 addiction treatment centers and included individuals in treatment for alcohol use, had in-treatment data, and screened positive for anxiety (n = 6147) or depressive symptoms (n = 6197) at intake. Anxiety and depressive symptoms were measured weekly during the first month of treatment. Three trajectories of anxiety symptoms (i.e., Persistent Moderate Anxiety Symptoms, Remitting Moderate Anxiety Symptoms, and Remitting Mild Anxiety Symptoms) and depressive symptoms (i.e., Increasing Moderate Depressive Symptoms, Persistent Moderate Depressive Symptoms, and Remitting Mild Depressive Symptoms) were identified. Women, younger individuals, and individuals who endorsed greater past month benzodiazepine use and depressive symptoms at intake were more likely to be in the Persistent Moderate Anxiety Symptoms trajectory relative to the Remitting Mild Anxiety Symptoms subgroup. Women, individuals who screened positive for anxiety at intake, and individuals reporting past month heroin use were more likely to be in the Increasing Moderate Depressive Symptoms trajectory relative to the Remitting Mild Depressive Symptom trajectory. Trajectories characterized by persistent moderate anxiety and depressive symptoms during the first month of treatment were more likely to drop out of treatment compared to individuals who reported low symptom levels. Findings indicate heterogeneity in the clinical course of anxiety and depressive symptoms among individuals in treatment for alcohol use and highlight that persistently high anxiety and depressive symptoms may pose an impediment to successful treatment completion. Results also demonstrate the importance of considering demographic and clinical characteristics at treatment intake as they may have significant implications for the unfolding of anxiety and depressive symptoms during treatment and subsequent outcomes.

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

Social vulnerability, COVID-19 impact, and decision making among adults in a low-resource community.

Socially vulnerable individuals, including those with greater exposure to adversity and social instability, are at greater risk for a variety of negative outcomes following exposure to public health crises. One hypothesized mechanism linking social vulnerability to poor health outcomes is delay discounting, the behavioral tendency to select smaller immediately available rewards relative to larger delayed rewards. However, little research has examined the impact of real-world disease outbreaks, such as the COVID-19 pandemic, on the relation between social vulnerability and delay discounting. This study examined whether the severity of COVID-19 impact moderated the association between social vulnerability and delay discounting in a diverse sample of 72 human adults (Mage = 42.4; 69% Black; 87% female) drawn from two low-resource urban areas. Contrary to hypotheses, results indicated that exposure to more severe COVID-19 impacts did not affect decision making among individuals with higher levels of social vulnerability. Conversely, findings suggest that individuals with lower levels of social vulnerability who reported more significant impacts of COVID-19 evidenced a greater tendency to select larger, delayed rewards relative to individuals with greater social vulnerability. Findings suggest the recent pandemic may influence the relation between social vulnerability and behavioral processes underlying health decision-making.

Adverse childhood experiences and comorbidity in a cohort of people who have injected drugs.

BACKGROUND: Childhood adversity is associated with the onset of harmful adult substance use and related health problems, but most research on adversity has been conducted in general population samples. This study describes the prevalence of adverse childhood experiences in a cohort of people who have injected drugs and examines the association of these adverse experiences with medical comorbidities in adulthood. METHODS: Six hundred fifty three adults were recruited from a 30-year cohort study on the health of people who have injected drugs living in and around Baltimore, Maryland (Median age = 47.5, Interquartile Range = 42.3-52.3 years; 67.3% male, 81.1% Black). Adverse childhood experiences were assessed retrospectively in 2018 via self-report interview. Lifetime medical comorbidities were ascertained via self-report of a provider diagnosis. Multinomial logistic regression with generalized estimating equations was used to examine the association between adversity and comorbid conditions, controlling for potential confounders. RESULTS: Two hundred twelve participants (32.9%) reported 0-1 adverse childhood experiences, 215 (33.3%) reported 2-4, 145 (22.5%) reported 5-9, and 72 (11.1%) reported ≥10. Neighborhood violence was the most commonly reported adversity (48.5%). Individuals with ≥10 adverse childhood experiences had higher odds for reporting ≥3 comorbidities (Adjusted Odds Ratio = 2.9, 95% CI = 1.2 - 6.8, p = .01). CONCLUSIONS: Among people who have injected drugs, adverse childhood experiences were common and associated with increased occurrence of self-reported medical comorbidities. Findings highlight the persistent importance of adversity for physical health even in a population where all members have used drugs and there is a high burden of comorbidity.

Epigenome-wide association analyses of active injection drug use.

BACKGROUND: Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized. METHODS: 401 participants (Mage = 47.9; 68% male; 90% African American) over several timepoints (1054 visits) were drawn from a longitudinal cohort of people who inject drugs. DNA methylation was measured among buffy coat samples from the 1054 visits. Compared to samples collected after ≥ 6 months of abstinence, separate EWAS were conducted for active injecting of any drug, quantitative injection frequency, injecting of heroin and injecting of cocaine. Linear mixed effect models were used and analyses were adjusted for repeated measurements and key technical, biological, and sociodemographic characteristics. RESULTS: We found epigenome-wide significant CpG sites associated with active injection (cg10636246, AIM2, p = 2.33 × 10-8) and injection intensity (cg13117953, p = 4.30 × 10-8). We found converging evidence that cg10636246 (AIM2), cg23110600 (PRKCH), cg03546163 (FKBP5), cg04590956 (GMCL1), and cg16317961 (MAPRE2) were among the top 0.1% significantly differentially methylated CpG sites shared across the five EWAS. Top ranked CpGs among the five EWAS were enriched (p < 0.0001) in AIM2 inflammasome complex, T cell migration, insulin regulation and epinephrine synthesis pathways. During periods of active injection, samples had 0.46 years of epigenetic age acceleration relative to the abstinence period, within the same subject (p = 0.03). CONCLUSIONS: Findings from this study demonstrate modest, common, and specific effects on DNA methylation during a relatively short time between periods of active drug injection and abstinence.

Positive associations between cannabis and alcohol use polygenic risk scores and phenotypic opioid misuse among African-Americans.

BACKGROUND: This study examined whether polygenic risk scores (PRS) for lifetime cannabis and alcohol use were associated with misusing opioids, and whether sex differences existed in these relations in an urban, African-American sample. METHODS: Data were drawn from three cohorts of participants (N = 1,103; 45% male) who were recruited in first grade as part of a series of elementary school-based, universal preventive intervention trials conducted in a Mid-Atlantic region of the U.S. In young adulthood, participants provided a DNA sample and reported on whether they had used heroin or misused prescription opioids in their lifetime. Three substance use PRS were computed based on prior GWAS: lifetime cannabis use from Pasman et al. (2018), heavy drinking indexed via maximum number of drinks from Gelernter et al. (2019), and alcohol consumption from Kranzler et al. (2019). RESULTS: Higher PRS for lifetime cannabis use, greater heavy drinking, and greater alcohol consumption were associated with heightened risk for misusing opioids among the whole sample. Significant sex by PRS interactions were also observed such that higher PRS for heavy drinking and alcohol consumption were associated with a greater likelihood of opioid misuse among males, but not females. CONCLUSION: Our findings further elucidate the genetic contributions to misusing opioids by showing that the genetics of cannabis and alcohol consumption are associated with lifetime opioid misuse among young adults, though replication of our findings is needed.

Individual and Combined Association Between Prenatal Polysubstance Exposure and Childhood Risk of Attention-Deficit/Hyperactivity Disorder.

Importance: Polysubstance use among pregnant women has increased because of the opioid epidemic and the increasing legalization of cannabis along with persistent tobacco and alcohol consumption. Previous research on prenatal substance use and the child's risk of attention-deficit/hyperactivity disorder (ADHD) has mostly focused on single-substance exposures; simultaneous examination of multiple substance use and assessment of their synergistic health consequences is needed. Objectives: To assess the consequences of the use of specific substances during pregnancy, investigate whether the interaction of multiple prenatal substance exposures is associated with increases in the risk of childhood ADHD, and estimate the aggregate burden of polysubstance exposure during gestation. Design, Setting, and Participants: This cohort study analyzed data from the Boston Birth Cohort from 1998 to 2019. The sample of the present study comprised a multiethnic urban cohort of mother-child pairs who were predominantly low income. A total of 3138 children who were enrolled shortly after birth at Boston Medical Center were included and followed up from age 6 months to 21 years. Exposures: Substance use during pregnancy was identified based on self-reported tobacco smoking, alcohol consumption, and use of cannabis, cocaine, or opioids in any trimester of pregnancy. Diagnostic codes for neonatal opioid withdrawal syndrome or neonatal abstinence syndrome from the International Classification of Diseases, Ninth Revision, and the International Classification of Diseases, Tenth Revision, were also used to identify opioid exposure during gestation. Main Outcomes and Measures: ADHD diagnosis in the child's electronic medical record. Results: Among 3138 children (1583 boys [50.4%]; median age, 12 years [IQR, 9-14 years]; median follow-up, 10 years [IQR, 7-12 years]) in the final analytic sample, 486 (15.5%) had an ADHD diagnosis and 2652 (84.5%) were neurotypical. The median postnatal follow-up duration was 12 years (IQR, 9-14 years). Among mothers, 46 women (1.5%) self-identified as Asian (non-Pacific Islander), 701 (22.3%) as Hispanic, 1838 (58.6%) as non-Hispanic Black, 227 (7.2%) as non-Hispanic White, and 326 (10.4%) as other races and/or ethnicities (including American Indian or Indigenous, Cape Verdean, Pacific Islander, multiracial, other, or unknown). A total of 759 women (24.2%) reported the use of at least 1 substance during pregnancy, with tobacco being the most frequently reported (580 women [18.5%]). Cox proportional hazards models revealed that opioid exposure (60 children) had the highest adjusted hazard ratio (HR) for ADHD (2.19; 95% CI, 1.10-4.37). After including main statistical effects of all individual substances in an elastic net regression model, the HR of opioids was reduced to 1.60, and evidence of a statistical interaction between opioids and both cannabis and alcohol was found, producing 1.42 and 1.15 times higher risk of ADHD, respectively. The interaction between opioids and smoking was also associated with a higher risk of ADHD (HR, 1.17). Conclusions and Relevance: The findings of this study suggest that it is important to consider prenatal concurrent exposure to multiple substances and their possible interactions when counseling women regarding substance use during pregnancy, the future risk of ADHD for their children, and strategies for cessation and treatment programs.

Differential expression of NPAS4 in the dorsolateral prefrontal cortex following opioid overdose.

Background: Although preclinical models reveal the neurobiological pathways altered through opioid abuse, comprehensive assessments of gene expression in human brain samples are needed. Moreover, less is known about gene expression in response to fatal overdose. The primary goal of the present study was to compare gene expression in the dorsolateral prefrontal cortex (DLPFC) between brain samples of individuals who died of acute opioid intoxication and group-matched controls. Methods: Postmortem tissue samples of the DLPFC from 153 deceased individuals (Mage  = 35.4; 62% male; 77% European ancestry). Study groups included 72 brain samples from individuals who died of acute opioid intoxication, 53 psychiatric controls, and 28 normal controls. Whole transcriptome RNA-sequencing was used to generate exon counts, and differential expression was tested using limma-voom. Analyses were adjusted for relevant sociodemographic characteristics, technical covariates, and cryptic relatedness using quality surrogate variables. Weighted correlation network analysis and gene set enrichment analyses also were conducted. Results: Two genes were differentially expressed in opioid samples compared to control samples. The top gene, NPAS4, was downregulated in opioid samples (log2FC = -2.47, adj. p = .049) and has been implicated in opioid, cocaine, and methamphetamine use. Weighted correlation network analysis revealed 15 gene modules associated with opioid overdose, though no intramodular hub genes were related to opioid overdose, nor were pathways related to opioid overdose enriched for differential expression. Conclusions: Results provide preliminary evidence that NPAS4 is implicated in opioid overdose, and more research is needed to understand its role in opioid abuse and associated outcomes.

Shared Genetic Etiology between Cortical Brain Morphology and Tobacco, Alcohol, and Cannabis Use.

Genome-wide association studies (GWAS) have identified genetic variants associated with brain morphology and substance use behaviors (SUB). However, the genetic overlap between brain structure and SUB has not been well characterized. We leveraged GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using linkage disequilibrium score regression. We used genomic structural equation modeling to model a "common SUB genetic factor" and investigated its genetic overlap with brain structure. Furthermore, we estimated SUB polygenic risk scores (PRS) and examined whether they predicted brain imaging traits using the Adolescent Behavior and Cognitive Development (ABCD) study. We identified 8 significant negative genetic correlations, including between (1) alcoholic drinks per week and average cortical thickness, and (2) intracranial volume with age of smoking initiation. We observed 5 positive genetic correlations, including those between (1) insula surface area and lifetime cannabis use, and (2) the common SUB genetic factor and pericalcarine surface area. SUB PRS were associated with brain structure variation in ABCD. Our findings highlight a shared genetic etiology between cortical brain morphology and SUB and suggest that genetic variants associated with SUB may be causally related to brain structure differences.

Early Childhood Behavioral and Academic Antecedents of Lifetime Opioid Misuse among Urban Youth.

OBJECTIVE: Opioid misuse has become an epidemic in the United States. In the present study, we examine potential malleable early childhood predictors of opioid misuse including whether childhood achievement, aggressive behavior, attention problems, and peer social preference/likability in first grade predicted opioid misuse and whether these relationships differed depending on participant sex. METHOD: Data are drawn from three cohorts of participants (N = 1,585; 46.7% male) recruited in first grade as part of a series of elementary school-based, universal preventive interventions conducted in a Mid-Atlantic region of the US. In first grade, participants completed standardized achievement tests, teachers reported on attention problems, and peers nominated their classmates with respect to their aggressive behavior and social preference/likability. At approximately age 20, participants reported on their misuse of opioids defined as lifetime use of heroin or misuse of prescription opioids. RESULTS: Higher levels of peer nominations for aggressive behavior in first grade predicted a greater likelihood of opioid misuse. An interaction between participant sex and attention problems was observed such that females higher in attention problems were more likely to misuse opioids, particularly prescription opioids, than females lower in attention problems. An interaction was also found between participant sex and peer likability such that males lower in peer-nominated likability were more likely to misuse opioids relative to males higher in likability. CONCLUSION: Given the malleable nature of attention problems, aggression, and social skills in early childhood, prevention programs that target these behaviors during this developmental period may attenuate risk for opioid misuse.

Associations of adverse childhood experiences with adolescent total sleep time, social jetlag, and insomnia symptoms.

STUDY OBJECTIVE: Adverse childhood experiences (ACEs) are associated with sleep problems in adulthood, but less research has focused on ACEs and sleep during adolescence. The goal of the present study was to explore associations between ACEs reported at ages 5 and 9 years, and sleep (ie, total sleep time (TST), social jetlag, and insomnia symptoms) at age 15. METHODS: Participants comprised 817 families from the Fragile Families and Child Wellbeing Study, a nationally representative sample of children born to unwed parents. Number of ACEs was constructed from primary-caregiver reports at ages 5 and 9, and sleep measures (ie, TST, social jetlag, and insomnia symptoms) were derived from adolescent-reported sleep behaviors at age 15. RESULTS: Adjusting for sex and race/ethnicity, ACEs at age 9 were associated with longer weekend TST (B = 0.16, 95% CI = 0.04, 0.28), more social jetlag (B = 0.17, 95% CI = 0.07, 0.27), and higher odds of trouble falling asleep ≥3 times per week (Odds Ratio = 1.24, 95% CI = 1.01, 1.53). In females only, ACEs were associated with greater school night TST (B = 0.12, 95% CI = 0.01, 0.23). Results were similar after further adjustment for symptoms of anxiety and depression. Associations among ACEs, social jetlag, and insomnia symptoms appeared strongest among Non-Hispanic Black adolescents. CONCLUSION: ACEs appear to be related to multiple aspects of sleep in adolescence. Additional research is needed to confirm these associations and examine the extent to which sleep disturbances associated with ACEs account for later health outcomes.

Genetic propensity for risky behavior and depression and risk of lifetime suicide attempt among urban African Americans in adolescence and young adulthood.

Suicide attempts (SA) among African Americans have increased at a greater rate than any other racial/ethnic group. Research in European ancestry populations has indicated that SA are genetically influenced; however, less is known about the genetic contributors that underpin SA among African Americans. We examined whether genetic propensity for depression and risky behaviors (assessed via polygenic risk scores; PRS) independently and jointly are associated with SA among urban, African Americans and whether sex differences exist in these relations. Participants (N = 1,157, 45.0% male) were originally recruited as part of two first grade universal school-based prevention trials. Participants reported in adolescence and young adulthood on whether they ever attempted suicide in their life. Depression and risky behaviors PRS were created based on large-scale genome-wide association studies conducted by Howard et al. (2019) and Karlson Línner et al. (2019), respectively. There was a significant interaction between the risky behavior PRS and depression PRS such that the combination of high risky behavior polygenic risk and low/moderate polygenic risk for depression was associated with greater risk for lifetime SA among the whole sample and African American males specifically. In addition, the risky behavior PRS was significantly positively associated with lifetime SA among African American males. These findings provide preliminary evidence regarding the importance of examining risky behavior and depression polygenic risk in relation to SA among African Americans, though replication of our findings in other African American samples is needed.