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The heritability of substance dependence (SD) liability is based on polymorphisms at the genes that are likely to be related to the function of the central nervous systern. We have recently shown an association between the dopamine DS receptor gene and SD liability. We report herein a replication of this association in an independent case-control sample. [ABSTRACT FROM AUTHOR]

Background: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene.Methods: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6.Results: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9)); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child.Conclusions: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling. [ABSTRACT FROM AUTHOR]

Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction-associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease.

Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWASs) 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 correcting for multiple testing using a two-stage procedure. We found >2 million significant meQTL variants (p adj  < 0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects, and five meQTLs, mapping to NUDT12, FAM53B, RNF39, and ADRA1B, showed a significant interaction with smoking. We found 57,683 significant eQTL variants for 958 unique eGenes (p adj  < 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 MUSTN1 and ITIH4 colocalized across all data types (GWAS, meQTL, and 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., (© 2024. The Author(s).)

Background: Inadequate sleep is associated with all-cause mortality in the general population. Substance use has adverse effects on sleep, and insomnia symptoms are common among people with HIV. Therefore, persons who inject drugs may face a heightened risk of adverse outcomes from inadequate sleep. We evaluated the association of inadequate sleep with mortality among persons who inject drugs in a long-standing community cohort., Methods: Participants were from the AIDS Linked to the IntraVenous Experience (ALIVE) study, a cohort of persons who inject drugs in Baltimore, Maryland, USA. From 2005-2020, perceived sleep adequacy and duration were assessed semiannually using survey. Mortality data were obtained through linkage to the National Death Index-Plus. Cause of death was independently characterized and validated by three physicians. Hazards of all-cause and cause-specific mortality were evaluated using Cox regression accounting for repeated measurements., Results: A total of 2633 participants were included, with a median age at entry of 45.8years; 32.5% were female, and 75% were Black. After adjustment for demographics, mental health, and comorbidities, inadequate sleep was associated with a 32% greater hazard of all-cause mortality (hazard ratio: 1.32, 95% confidence interval: 1.12-1.55) and a 67% greater hazard of HIV/infectious disease-related deaths (hazard ratio: 1.67, 95% confidence interval: 1.15-2.42). Short (<6 hours) and long (≥8 hours) duration of sleep were both associated with higher hazard of all-cause and chronic disease-related mortality (all p < .05)., Conclusions: Sleep plays a critical role in longevity in persons who inject drugs. Research is needed to determine whether interventions targeting sleep improve health and longevity in persons who inject drugs., Competing Interests: Declaration of conflicts of interest Adam Spira received payment for serving as a consultant for Merck, received honoraria from Springer Nature Switzerland AG for guest editing special issues of Current Sleep Medicine Reports, and is a paid consultant to Sequoia Neurovitality, BellSant, Inc, and Amissa, Inc. No other conflict of interest is reported., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., (©Amanda Luken, Jill A Rabinowitz, Jonathan L Wells, David W Sosnowski, Justin C Strickland, Johannes Thrul, Gregory D Kirk, Brion S Maher. Originally published in JMIR Formative Research (https://formative.jmir.org), 27.02.2024.)

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.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings., (© 2024. The Author(s).)

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., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest No potential conflict of interest reported by the author(s)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.

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 (r g  > 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., (© 2022. The Author(s).)

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 (M age = 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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 (M age = 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., (© 2022. The Author(s).)

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., Competing Interests: The authors report no conflicts of interest.

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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 ( M age  = 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 (log 2 FC = -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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s). Published by Elsevier B.V.)

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.

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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2021 Wiley Periodicals LLC.)

Background: Opioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of opioid abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. To clarify the association between opioid abuse and DNA methylation, we conducted an epigenome-wide analysis of DNA methylation in brain samples of individuals who died from acute opioid intoxication and group-matched controls., Methods: Tissue samples were extracted from the dorsolateral prefrontal cortex of 153 deceased individuals (M age = 35.42; 62 % male; 77 % European ancestry). The study included 72 opioid samples, 53 psychiatric controls, and 28 normal controls. The epigenome-wide analysis was implemented using the Illumina MethylationEPIC BeadChip; analyses adjusted for sociodemographic characteristics, negative control principal components, ancestry principal components, cellular composition, and surrogate variables. Horvath's epigenetic age and Levine's PhenoAge were calculated, and gene set enrichment analyses were performed., Results: Although no CpG sites survived false-discovery rate correction for multiple testing, 13 sites surpassed a relaxed significance threshold (p < 1.0 × 10 -5 ). One of these sites was located within Netrin-1, a gene implicated in kappa opioid receptor activity. There was an association between opioid use and accelerated PhenoAge (b = 2.24, se = 1.11, p = .045). Gene set enrichment analyses revealed enrichment of differential methylation in GO and KEGG pathways broadly related to substance use., Conclusions: Netrin-1 may be associated with opioid overdose, and future research with larger samples across stages of opioid use will elucidate the complex genomics of opioid abuse., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Cannabis, tobacco and alcohol use are prevalent among youth in the United States and may be risk factors for opioid use. The current study aimed at investigating associations between developmental trajectories of cannabis, tobacco and alcohol use in adolescence and opioid use in young adulthood in an urban cohort over the span of 12 years., Design: Cohort study of adolescents originally recruited for a randomized prevention trial with yearly assessments into young adulthood., Setting: Nine urban elementary schools in Baltimore, MD in the United States., Participants: Participants (n = 583, 86.8% African American, 54.7% male) were originally recruited as first grade students., Measurements: Cannabis, tobacco and alcohol use were assessed annually from ages 14-18 years and opioid use from ages 19-26. Socio-demographics were assessed at age 6. Intervention status was also randomly assigned at age 6. Gender, race, free/reduced-priced lunch and intervention status were included as covariates in individual and sequential growth models., Findings: There were significant positive associations between the cannabis use intercept at age 14 and the opioid use intercept at age 19 (beta = 1.43; P = 0.028), the tobacco use intercept at age 14 and the opioid use intercept at age 19 (beta = 0.82; P = 0.042). Specifically, more frequent use of cannabis or tobacco at age 14 was associated with more frequent use of opioids at age 19., Conclusions: Cannabis and tobacco use in early adolescence may be risk factors for opioid use in young adulthood among African Americans living in urban areas., (© 2020 Society for the Study of Addiction.)

Background: The opioid epidemic is a public health emergency in the US. Alcohol is the most widely used addictive substance among all age groups; however, the contribution of different alcohol use trajectories throughout adolescence and young adulthood to the development of opioid misuse in young adulthood among urban minority youth has not been investigated. Methods: Data are from a study of 580 youth (85% African American, 67% low SES) residing in Baltimore City followed from ages 6-26. Alcohol trajectories were identified between ages 14 and 26 using group-based trajectory modeling. Opioid misuse was defined as using opioid painkillers without a prescription or using heroin between ages 19 and 26. Opioid misuse outcomes were also investigated separately. Logistic regression examined associations of alcohol trajectories with opioid misuse in young adulthood adjusting for socio-demographics, early use of tobacco and cannabis, neighborhood, and peer factors. Results: Six alcohol use trajectories were identified: Young adult increasing (21.4%), adult increasing (19.1%), abstaining (19.1%), experimenting (15.3%), adolescent increasing (14.8%), and adolescent limited (10.2%). In models fully adjusted for covariates, relative to the abstaining trajectory, the adolescent increasing trajectory was associated with an elevated risk of opioid misuse (aOR = 3.3, 95%CI = 1.4, 7.8) and prescription opioid misuse (aOR = 3.9, 95%CI = 1.4, 10.8) in young adulthood. Conclusions: Escalating alcohol use in adolescence and young adulthood is associated with an elevated risk of opioid misuse in young adulthood in a cohort of predominantly African American and socio-economically disadvantaged young people. Tailored interventions should target high levels of alcohol use during these developmental periods to reduce risk for opioid misuse among disadvantaged youth.

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