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DSM-V-defined substance use disorder comprises four groups of symptoms: impaired control, social impairment, risky use, and pharmacological reactions. Behavioral patterns of impaired control, including impulsivity and risk taking, are associated with HIV risk behaviors. Substance users with stronger craving symptoms are more likely to use drugs via intravenous injection than other routes because of the faster drug effect and the higher bioavailability; thus, they are at high risk of HIV infection. HIV risk behaviors such as unprotected sex and intravenous injection facilitate HIV disease spread. Public health policies such as Needle and Syringe Exchange Programs and medication-assisted treatment are proven to reduce HIV risk behaviors such as the frequency of intravenous injection and even the incidence of HIV infection, but both of them have limitations. While intravenous injection is a frequently discussed issue in public policies and the HIV-related literature, it is a much less frequent topic in the addiction literature. We believed that understanding the mental substrate behind impulsivity/risk taking and the possible biological mechanism of intravenous injection may help in creating more effective strategies to slow down HIV infection.

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. 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). 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. 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.

Anxiety disorders (ADs) are common mental disorders caused by a combination of genetic and environmental factors. Since ADs are highly comorbid with each other, partially due to shared genetic basis, studying AD phenotypes in a coordinated manner may be a powerful strategy for identifying potential genetic loci for ADs. To detect these loci, we performed genome-wide association studies (GWAS) of ADs. In addition, as a complementary approach to single-locus analysis, we also conducted gene- and pathway-based analyses. GWAS data were derived from the control sample of the Molecular Genetics of Schizophrenia (MGS) project (2,540 European American and 849 African American subjects) genotyped on the Affymetrix GeneChip 6.0 array. We applied two phenotypic approaches: (1) categorical case-control comparisons (CC) based upon psychiatric diagnoses, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. Linear and logistic models were used to analyse the association with ADs using FS and CC traits, respectively. At the single locus level, no genome-wide significant association was found. A trans-population gene-based meta-analysis across both ethnic subsamples using FS identified three genes (MFAP3L on 4q32.3, NDUFAB1 and PALB2 on 16p12) with genome-wide significance (false discovery rate (FDR] <5%). At the pathway level, several terms such as transcription regulation, cytokine binding, and developmental process were significantly enriched in ADs (FDR <5%). Our approaches studying ADs as quantitative traits and utilizing the full GWAS data may be useful in identifying susceptibility genes and pathways for ADs.

Introduction Insufficient sleep is associated with all-cause mortality in the general population. Illicit drugs have pronounced effects upon sleep, and insomnia symptoms are common among people with HIV (PWH), suggesting persons who inject drugs (PWID) with HIV may be at higher risk of adverse outcomes from insufficient sleep. Methods Participants in the AIDS Linked to the IntraVenous Experience (ALIVE) study, a cohort of PWID with or without HIV, completed the Sleep Adequacy subscale of the Medical Outcomes Study (MOS) semi-annually from 2005-present. Two questions queried participants about the frequency over the past four-weeks of: 1. getting sufficient sleep to feel rested on awakening; 2. obtaining needed amount of sleep. Six-Item responses ranged from “all of the time” to “none of the time”. Participants with mean subscale scores below the sample median were considered to have insufficient sleep. Mortality data were obtained through the National Death Index through 2018. Hazards of all-cause and cause-specific mortality were evaluated using Cox-regressions accounting for repeated measurements of insufficient sleep, respectively. Models were adjusted for sociodemographics, HIV and HCV infection, severe depressive symptoms (Center for Epidemiological Studies Depression [CESD]≥23), number of comorbidities (0, 1, ≥2), active injection drug use, current tobacco and alcohol use. Results Of 2612 participants (33% HIV+), mean age at baseline was 45.8 years, 32.4% were female, 75% Black, 45% had ≥high school education, and 33% had an annual income >$5,000. At baseline, the majority were current smokers (84%), alcohol drinkers (59%), or actively injecting drugs (56%), while 25% had severe depressive symptoms and 21% had ≥2 comorbidities. After adjustment for covariates, insufficient sleep was associated with a 37% increased hazard of all-cause mortality (HR: 1.37, 95% confidence interval [CI]: 1.13–1.65). Insufficient sleep was associated with a 93% increased hazard of death from HIV or infectious disease-related deaths (HR: 1.93, 95% CI: 1.26–2.97). Conclusion Insufficient sleep was independently associated with all-cause mortality and specifically with death from HIV or infectious diseases-related causes among PWID. Interventions consider targeting sleep behaviors among PWID hold promise for improving health and longevity in this population. Support (if any) National Institutes of Health grants: U01-DA-036297; R01-DA-047064; R01-HL-90483; K24-AI-118591; T32-DA007292; R01-DA039408.

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.

Obsessive–compulsive disorder (OCD) affects 1–2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case–control analyses ( n  = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4–22.5, P  = 2.3 × 10 −6 ). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P  = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P  = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P  = 7.33 × 10 −3 ). These data support a contribution of rare coding variants to OCD genetic risk. An analysis of the largest exome sequencing dataset of people with obsessive–compulsive disorder to date ( n  = 1,313 affected individuals), where both case–control and de novo variant studies support a contribution of rare damaging coding variants to risk.

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.

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.

We examined whether the interplay between community disadvantage and a conduct disorder polygenic risk score (CD PRS) was associated with sexual health outcomes among urban women. Participants (N = 511; 75.5% African American) were originally recruited to participate in a school-based intervention and were followed into adulthood. Community disadvantage was calculated using census data when participants were in first grade. At age 20, blood or saliva samples were collected and participants reported on their condom use, sexual partners, and sexually transmitted infections. A CD PRS was created based on a genome-wide association study conducted by Dick et al. [2010]. Higher levels of community disadvantage was associated with greater sexually transmitted infections among women with a higher CD PRS. Implications of the study findings are discussed.

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.