Opiate/opioid use disorder (OUD) is a chronic relapsing brain disorder that has increased in prevalence in the last two decades in the United States. Understanding the molecular correlates of OUD may provide key insights into the pathophysiology of this syndrome. Using publicly available RNA-sequencing data, our study investigated the possible role of alternative mRNA splicing in human brain tissue (dorsal–lateral prefrontal cortex (dlPFC), nucleus accumbens (NAc), and midbrain) of 90 individuals with OUD or matched controls. We found a total of 788 differentially spliced genes across brain regions. Alternative mRNA splicing demonstrated mostly tissue-specific effects, but a functionally characterized splicing change in the clathrin and AP-2-binding (CLAP) domain of the Bridging Integrator 1 (BIN1) gene was significantly linked to OUD across all brain regions. We investigated two hypotheses that may underlie differential splicing in OUD. First, we tested whether spliceosome genes were disrupted in the brains of individuals with OUD. Pathway enrichment analyses indicated spliceosome perturbations in OUD across brain regions. Second, we tested whether alternative mRNA splicing regions were linked to genetic predisposition. Using a genome-wide association study (GWAS) of OUD, we found no evidence that DNA variants within or surrounding differentially spliced genes were implicated in the heritability of OUD. Altogether, our study contributes to the understanding of OUD pathophysiology by providing evidence of a possible role of alternative mRNA splicing in OUD.
African Americans have elevated substance use-related problems during adulthood despite initiating use later than individuals of other racial/ethnic backgrounds. The present study first validated the structure of the UPPS-P Impulsive Behavior Scale and then examined impulsivity as a prospective risk factor for future alcohol, cannabis, and tobacco use, as well as generalized substance problems, in African American men. Data were drawn from the African-American Men's Project, which recruited participants (NWAVE-1 = 504; Mean ageWAVE-1 = 20.7; NWAVE-3 = 379; Mean ageWAVE-3 = 23.6) from rural counties of Georgia. Participants responded to an adapted version of the UPPS-P at Wave 1. Confirmatory factor analyses determined that a 5-factor model of impulsivity and a 3-factor hierarchical model of impulsivity described the data equally well, in comparison to 1-factor, 4-factor, or bifactor models. This supports that the structure of the abbreviated UPPS-P in African Americans is likely consistent with observations in White, Hispanic/Latino, and admixed samples. Notably, all second-order factors of the UPPS-P are not alike in predicting substance use outcomes when examined jointly in African American men. Only Deficits in Conscientiousness, which is a second-order factor comprised of Lack of Premeditation and Lack of Perseverance, affected whether individuals met any criteria for future substance use problems. Our findings provide novel insight into the relationship between impulsivity and substance involvement during emerging adulthood in African American men.
Background: Rodent paradigms and human genome-wide association studies (GWAS) on drug use have the potential to provide biological insight into the pathophysiology of addiction. Methods: Using GeneWeaver, we created rodent alcohol and nicotine gene-sets derived from 19 gene expression studies on alcohol and nicotine outcomes. We partitioned the SNP heritability of these gene-sets using four large human GWAS: (1) alcoholic drinks per week, (2) problematic alcohol use, (3) cigarettes per day, and (4) smoking cessation. We benchmarked our findings with curated human alcohol and nicotine addiction gene-sets and performed specificity analyses using other rodent gene-sets (e.g., locomotor behavior) and other human GWAS (e.g., height). Results: The rodent alcohol gene-set was enriched for heritability of drinks per week, cigarettes per day, and smoking cessation, but not problematic alcohol use. However, the rodent nicotine gene-set was not significantly associated with any of these traits. Both rodent gene-sets showed enrichment for several non-substance-use GWAS, and the extent of this relationship tended to increase as a function of trait heritability. In general, larger gene-sets demonstrated more significant enrichment. Finally, when evaluating human traits with similar heritabilities, both rodent gene-sets showed greater enrichment for substance use traits. Conclusion: Our results suggest that rodent gene expression studies can help to identify genes that contribute to the heritability of some substance use traits in humans, yet there was less specificity than expected. We outline various limitations, interpretations, and considerations for future research.
The multitude of gambling activities has given rise to heterogeneous ways of analyzing these behaviors and may partially underlie the lack of replication in gambling research. The current study used complementary analyses to investigate the structure, typology and etiology of gambling behaviors in a discovery sample of 2,116 twins (54.86% female; Mage = 24.90) and a replication sample of 619 siblings (30.37% female; Mage = 28.00). Our approach was twofold. First, we used confirmatory factor analyses to investigate the structure across the frequency of eight gambling activities. Second, we used factor mixture models to identify gambling frequency subtypes. We assessed associations with gambling frequency as well as conducted genetically informed analyses to estimate the role of genetic and environmental influences. Across samples, a two-factor model fit the data best, with a Common Gambling factor influencing all activities and a separate factor for Skill Gambling. Our study identified four gambling frequency subtypes, which resembled the typology from the Pathways Model. We found distinct demographic, psychiatric, behavioral and genetic risk profiles for the different gambling factors and subtypes with robust associations observed for male sex, risk-taking, sensation seeking, alcohol dependence and problem gambling. Controlling for shared genetic and environmental influences (via co-twin control modeling), we found that sensation seeking directly increased Common Gambling frequency. In sum, we illustrated the utility of multi-dimensional statistical techniques for disentangling the structure and typology from complex multivariate gambling data.
This research examines the relationship between smoking during pregnancy (SDP) and risk for reading related problems in siblings discordant for exposure to SDP. Data (N = 173 families) were drawn from the Missouri Mothers and Their Children study, a sample, identified using birth records (years 1998–2005), in which mothers changed her smoking behavior between two pregnancies (Child 1 [older sibling]: M = 12.99; Child 2 [younger sibling]: M = 10.19). A sibling comparison approach was used, providing a robust test for the association between SDP and reading related outcomes in school-aged children. Results suggested within-family (i.e., potentially causal) associations between SDP and reading and language/comprehension factor scores, as well as between SDP and specific reading-related skills, including reading accuracy and receptive language, with increased exposure to SDP associated with decreased performance. SDP was not associated with spelling, reading rate, or receptive vocabulary. Initial within-family associations between SDP and word-letter identification, phonetic/decoding skills, and reading comprehension were fully attenuated following partial control for genetic and environmental confounding of the associations. These findings indicate that exposure to SDP is associated with poorer performance on some, but not all skills assessed.
Cocaine use presents a worldwide public health problem with high socioeconomic cost. No current pharmacologic treatments are available for cocaine use disorder (CUD) or cocaine toxicity. To explore pharmaceutical treatments for tthis disorder and its sequelae we analyzed gene expression data from post-mortem brain tissue of individuals with CUD who died from cocaine-related causes with matched cocaine-free controls (n = 71, Mage = 39.9, 100% male, 49% with CUD, 3 samples/brain regions). To match molecular signatures from brain pathology with potential therapeutics, we leveraged the L1000 database honing in on neuronal mRNA profiles of 825 repurposable compounds (e.g., FDA approved). We identified 16 compounds that were negatively associated with CUD gene expression patterns across all brain regions (padj < 0.05), all of which outperformed current targets undergoing clinical trials for CUD (all padj > 0.05). An additional 43 compounds were positively associated with CUD expression. We performed an in silico follow-up potential therapeutics using independent transcriptome-wide in vitro (neuronal cocaine exposure; n = 18) and in vivo (mouse cocaine self-administration; n = 12–15) datasets to prioritize candidates for experimental validation. Among these medications, ibrutinib was consistently linked with the molecular profiles of both neuronal cocaine exposure and mouse cocaine self-administration. We assessed the therapeutic efficacy of ibrutinib using the Drosophila melanogaster model. Ibrutinib reduced cocaine-induced startle response and cocaine-induced seizures (n = 61–142 per group; sex: 51% female), despite increasing cocaine consumption. Our results suggest that ibrutinib could be used for the treatment of cocaine use disorder.
Social support (SS) is typically associated with lower emotional distress (e.g., stress and depression) in individuals. However, SS is a multifaceted construct that can vary by quality, quantity (amount), and type (i.e., it can be emotional or instrumental in nature). Objective: The current study examined the relationships between characteristics of SS, stress, and depression in aging African Americans. Participants: Analyses focused on data from 705 participants aged 22–92 years from the Carolina African American Twin Study of Aging. Measurements: Measures included the quality and quantity of emotional and instrumental support received, as well as stress and depression. Design: A series of univariate and increasingly complex multivariate regression models were conducted in MPlus (using the cluster option to control for family structure) to examine the relationships between SS and emotional distress variables. Results: Overall, better quality of emotional SS predicted fewer depression symptoms and less perceived stress, after controlling for age, gender, socioeconomic status variables, and the other subtypes of SS. However, more instances of emotional SS were associated with higher levels of perceived stress, depression symptoms, and more stressful life events within the past year. Likewise, more instrumental SS predicted more perceived stress, while holding the other variables constant. Conclusion: African Americans who experience more emotional distress report more SS, but the quality of emotional support appears to play an important role in the association between reduced levels of stress and depression. These findings suggest that interventions should include approaches to reduce emotional distress as well as enhance the quality SS.
Cigarette smoking is associated with increased risk for myriad health consequences including cognitive decline and dementia, but research on the link between smoking and brain structure is nascent. In the current study, we assessed the relationship of cigarette smoking with gray matter (GM) and white matter (WM) in the UK Biobank, controlling for numerous confounding demographic and health variables. We used negative-binomial regression to model the association of cigarette smoking (having ever smoked regularly, cigarettes per day, and duration smoked) with GM and WM (GM N = 19,615; WM N = 17,760), adjusting for confounders. Ever smoked and duration were associated with smaller total GM volume. Ever smoked was associated with reduced volume of the right VIIIa cerebellum and elevated WM hyperintensity volume. Smoking duration was associated with reduced total WM volume. Regarding specific tracts, ever smoked was associated with reduced fractional anisotropy in the left cingulate gyrus part of the cingulum, left posterior thalamic radiation, and bilateral superior thalamic radiation, and increased mean diffusivity in the middle cerebellar peduncle, right medial lemniscus, bilateral posterior thalamic radiation, and bilateral superior thalamic radiation. This study identified significant associations of cigarette exposure with global measures of GM and WM, and select associations of ever smoked, but not cigarettes per day or duration, with specific GM and WM regions. By controlling for important sociodemographic and health confounders, such as alcohol use, this study identifies distinct associations between smoking and brain structure, highlighting potential mechanisms of risk for common neurological sequelae (e.g., dementia).
Background and Aims: Cannabis use (CU) is an etiologically complex behavior with several social, temperamental, neurocognitive, and behavioral precursors. Biometrical and molecular studies suggest an interplay of environmental and pleiotropic influences. However, it remains unclear whether identified genetic effects related to behavioral and temperamental characteristics have developmentally direct or indirect mechanisms on CU behavior. The Transmissible Liability Index (TLI) is a measure of continuous liability based on developmental precursors of substance use disorders. This study aimed to examine if the TLI plays a role in understanding genetic risk for CU behaviors. Design: Genome-wide association studies (n > 10 000; European Ancestry [EA]) of CU, risk tolerance, neuroticism, anxiety, and depression were used to construct polygenic scores (PGSs). Analyses assessed whether PGSs indirectly impacted risk for repeated use via TLI. Setting: United States of America. Participants: From Add Health study, 4077 individuals of EA age 11 to 21 during baseline interview collection. Measurements: Outcomes were initiation and repeated cannabis use (>5× in lifetime). The TLI was parameterized using a latent factor from 21 questions assessing for precursors of disordered use. Findings: The marker-based heritability of TLI, initiation, and repeated use were significant, but modest (14%, P = 0.033; 15%, P = 0.025; and 17%, P = 0.008, respectively). TLI and repeated use were genetically correlated (rg = 0.76, P = 0.033). The PGS for CU was associated with increased risk for repeated use and PGS for risk tolerance and depression were associated with TLI. Mediation analyses indicated significant, but very weak, indirect effects of PGS for risk tolerance and depression on repeated CU via the TLI. Conclusions: Adolescent behavioral and temperamental characteristics (i.e. the Transmissible Liability Index) appear to be early indicators of repeated cannabis use in adulthood. Although polygenic scores for cannabis use directly increased risk for repeated cannabis use, weak evidence was found for the role of polygenic scores of other internalizing/externalizing traits acting through adolescent derived Transmissible Liability Index on cannabis use behavior.
In utero cannabis exposure can disrupt fetal development and increase risk for various behavioral disruptions, including hyperactivity, inattention, delinquent behaviors, and later substance abuse, among others. This review summarizes the findings from contemporary investigations linking prenatal cannabis exposure to the development of psychopathology and identifies the limitations within the literature, which constrain our interpretations and generalizability. These limitations include a lack of genetic/familial control for confounding and limited data examining real world products, the full range of cannabinoids, and motives for use specifically in pregnant women. Taken together, our review reveals the need to continue to improve upon study designs in order to allow researchers to accurately draw conclusions about the development of behavioral consequences of prenatal cannabis exposure. Findings from such studies would inform policy and practices regarding cannabis use during pregnancy and move the field toward developing a comprehensive teratogenic profile of cannabis similar to what is characterized in the prenatal alcohol and tobacco literature.