Generalized genetic liability to substance use disorders.

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

Disentangling heterogeneity in substance use disorder: Insights from genome-wide polygenic scores.

Substance use disorder (SUD) is a global health problem with a significant impact on individuals and society. The presentation of SUD is diverse, involving various substances, ages at onset, comorbid conditions, and disease trajectories. Current treatments for SUD struggle to address this heterogeneity, resulting in high relapse rates. SUD often co-occurs with other psychiatric and mental health-related conditions that contribute to the heterogeneity of the disorder and predispose to adverse disease trajectories. Family and genetic studies highlight the role of genetic and environmental factors in the course of SUD, and point to a shared genetic liability between SUDs and comorbid psychopathology. In this study, we aimed to disentangle SUD heterogeneity using a deeply phenotyped SUD cohort and polygenic scores (PGSs) for psychiatric disorders and related traits. We explored associations between PGSs and various SUD-related phenotypes, as well as PGS-environment interactions using information on lifetime emotional, physical, and/or sexual abuse. Our results identify clusters of individuals who exhibit differences in their phenotypic profile and reveal different patterns of associations between SUD-related phenotypes and the genetic liability for mental health-related traits, which may help explain part of the heterogeneity observed in SUD. In our SUD sample, we found associations linking the genetic liability for attention-deficit hyperactivity disorder (ADHD) with lower educational attainment, the genetic liability for post-traumatic stress disorder (PTSD) with higher rates of unemployment, the genetic liability for educational attainment with lower rates of criminal records and unemployment, and the genetic liability for well-being with lower rates of outpatient treatments and fewer problems related to family and social relationships. We also found evidence of PGS-environment interactions showing that genetic liability for suicide attempts worsened the psychiatric status in SUD individuals with a history of emotional physical and/or sexual abuse. Collectively, these data contribute to a better understanding of the role of genetic liability for mental health-related conditions and adverse life experiences in SUD heterogeneity.

Exploring peripheral biomarkers in psychostimulant use: A systematic review on neurotrophins, stress-related hormones, oxidative stress molecules and genetic factors.

BACKGROUND: This systematic review aims to comprehensively explore the impact of psychostimulant substances on neurotrophic and inflammatory pathways, including brain-derived neurotrophic factor (BDNF), pro-BDNF, cortisol, dehydroepiandrosterone sulfate (DHEAS), thiobarbituric acid reactive substances (TBARS), interleukins, and the role of genetic factors. The study seeks to address existing gaps in the literature by providing a thorough evaluation of neurotrophic and inflammatory system alterations associated with different stages of psychostimulant dependence for a more nuanced understanding of substance use disorder (SUD) neurobiology. METHODS: A systematic review was conducted in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. The research encompasses 50 studies with a participant pool totaling 6792 individuals using psychostimulant substances. RESULTS: Key findings include diverse impacts of cocaine on BDNF levels, mainly consisting of their significant increase during withdrawal. In contrast, NGF showed an opposite behavior, reducing during withdrawal. Cortisol and DHEAS levels exhibited relevant increases after psychostimulant use, while TBARS showed conflicting results. Genetic investigations predominantly focused on the Val66Met polymorphism of the BDNF gene, revealing associations with susceptibility to stimulant addiction. CONCLUSIONS: Neurotrophins and inflammatory molecules play a significant role in the pathophysiological mechanisms following psychostimulant use. A better understanding of their complex interplay could aid clinicians in identifying biomarkers of different disease stages. Moreover, clinical interventions designed to interfere with neurotrophic and inflammatory pathways could possibly lead to craving-modulatory strategies and reduce pathological neuronal and systemic consequences of psychostimulant use.

An epigenetic candidate-gene association study of parental styles in suicide attempters with substance use disorders.

Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients.

SNP-based and haplotype-based genome-wide association on drug dependence in Han Chinese.

BACKGROUND: Drug addiction is a serious problem worldwide and is influenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese. METHODS: A total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping. RESULTS: Both single-SNP and haplotype tests revealed associations between illicit drug use and several immune-related genes in the major histocompatibility complex (MHC) region (SNP association: log10BF = 15.135, p = 1.054e-18; haplotype association: log10BF = 20.925, p = 2.065e-24). These genes may affect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide significant associations between rs3782886 (SNP association: log10BF = 8.726, p = 4.842e-11) in BRAP and rs671 (SNP association: log10BF = 7.406, p = 9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide significant association (haplotype association: log10BF = 7.607, p = 3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction. CONCLUSIONS: These findings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches.

The Potential and Challenges of Genomics Informed Precision Care for Substance Use Disorders.

Substance use disorders (SUDs) are complex brain disorders with heritability rooted in the interplay of multiple genetic factors, alongside significant environmental influences. Gaining insights into the genetic mechanisms that heighten SUD risk can guide precision care, specifically in the development of targeted tools for prevention, early intervention, and the discovery of therapeutic targets. Nurses are ideally placed to advance genomics-informed precision care for individuals with SUDs. To fulfill this role, they must be adequately prepared to assess the value and utility of current genomics knowledge, its limitations, and ways to incorporate this understanding into clinical practice, education, research, and health care policy. [Journal of Psychosocial Nursing and Mental Health Services, 62(3), 11-14.].

Pattern of Risks for Psychiatric and Substance Use Disorders in the Offspring of Parents With Alcohol Use Disorder.

OBJECTIVE: The authors sought to clarify the components of the familial liability to alcohol use disorder (AUD) by examining parent-offspring transmission in a large Swedish population sample. METHODS: To this end, 1,244,516 offspring in intact families with a mean age at follow-up of 37.7 years (SD=6.8) were examined. Hazard ratios for offspring of parents with AUD were calculated using Cox models for risk of five disorders assessed from Swedish medical and criminal registries: AUD, drug use disorders, attention deficit hyperactivity disorder, major depression, and anxiety disorders. RESULTS: The hazard ratio for the offspring was highest for AUD (hazard ratio=2.36), followed by drug use disorder (hazard ratio=2.04), attention deficit hyperactivity disorder (hazard ratio=1.82), major depression (hazard ratio=1.43), and anxiety disorder (hazard ratio=1.43). The risks for AUD were statistically indistinguishable between the children having mothers with AUD compared with those having fathers with AUD and between sons and daughters of a parent with AUD. All risks for offspring having two parents with AUD were higher than those having one parent with AUD, but the increase with two parents with AUD was greatest for AUD, followed by drug use disorder and attention deficit hyperactivity disorder. Age at AUD onset of the parents predicted risk among the offspring more strongly for AUD and drug use disorder, followed by attention deficit hyperactivity disorder, and then major depression and anxiety disorders. Number of recurrences of the parents with AUD predicted risks for all disorders equally. The risk pattern of disorders for the offspring of not-lived-with fathers with AUD was similar to that in the main analysis of intact families. No evidence was found for sex-specific transmission of AUD or a familial female protective effect. CONCLUSIONS: Familial and likely genetic liability to AUD has three components: a nonspecific risk of common internalizing and externalizing disorders, a moderately specific risk of externalizing disorders, and a highly specific risk of AUD.

It is not just about transcription: involvement of brain RNA splicing in substance use disorders.

Alternative splicing is a co-transcriptional process that significantly contributes to the molecular landscape of the cell. It plays a multifaceted role in shaping gene transcription, protein diversity, and functional adaptability in response to environmental cues. Recent studies demonstrate that drugs of abuse have a profound impact on alternative splicing patterns within different brain regions. Drugs like alcohol and cocaine modify the expression of genes responsible for encoding splicing factors, thereby influencing alternative splicing of crucial genes involved in neurotransmission, neurogenesis, and neuroinflammation. Notable examples of these alterations include alcohol-induced changes in splicing factors such as HSPA6 and PCBP1, as well as cocaine's impact on PTBP1 and SRSF11. Beyond the immediate effects of drug exposure, recent research has shed light on the role of alternative splicing in contributing to the risk of substance use disorders (SUDs). This is exemplified by exon skipping events in key genes like ELOVL7, which can elevate the risk of alcohol use disorder. Lastly, drugs of abuse can induce splicing alterations through epigenetic modifications. For example, cocaine exposure leads to alterations in levels of trimethylated lysine 36 of histone H3, which exhibits a robust association with alternative splicing and serves as a reliable predictor for exon exclusion. In summary, alternative splicing has emerged as a critical player in the complex interplay between drugs of abuse and the brain, offering insights into the molecular underpinnings of SUDs.

The predictive effect of family genetic risk scores as an indirect measure of causal effects of one disorder on another.

BACKGROUND: One potential cause of comorbidity is the direct causal effect of one disorder - A - on risk for subsequent onset of disorder B. Could genetic risk scores be utilized to test for such an effect? If disorder A causally impacts on risk for disorder B, then genetic risk for disorder A should be lower in cases of disorder A with v. without a prior onset of B. METHODS: In all individuals (n = 905 736) born in Sweden from 1980 to 1990, from six psychiatric and drug use disorders (major depression, anxiety disorders, alcohol use disorder, drug use disorder, bipolar disorder, and schizophrenia), we formed 14 pairs of disorders A and B. In these pairs, we compared, using Cox proportional hazards models, the predictive effect of the familial-genetic risk score (FGRS) for disorder B in those who had v. had not had a prior onset of disorder A. RESULTS: In all pairs, the impact of the FGRS for disorder B was significantly stronger in cases without v. with a prior history of disorder A. These effects were similar across sex, stable across levels of FGRS and not likely due to clinician bias. In many of our disorder pairs, previous clinical studies suggest a mechanism for a causal effect of disorder A on B. CONCLUSIONS: Our findings provide indirect evidence that the occurrence of one psychiatric or substance use disorder often has a causal effect on risk for subsequent disorders. This mechanism may substantially contribute to the widespread comorbidity among psychiatric conditions.

Associations of externalizing polygenic scores with externalizing disorders among Mexican youth.

Several studies have examined the association of externalizing polygenic scores (PGS) with externalizing symptoms in samples of European ancestry. However, less is known about the associations of externalizing polygenic vulnerability in relation to phenotypic externalizing disorders among individuals of different ancestries, such as Mexican youth. Here, we leveraged the largest genome-wide association study on externalizing behaviors that included over 1 million individuals of European ancestry to examine associations of externalizing PGS with a range of externalizing disorders in Mexican adolescents, and investigated whether adversity exposure in childhood moderated these associations. Participants (N = 1064; age range 12-17 years old; 58.8% female) were adolescents recruited for a general population survey on adolescent mental health in the Mexico City Metropolitan region and were genotyped. Childhood adversity exposure and externalizing disorders, specifically attention-deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, and substance use disorder, were assessed via the computer-assisted World Mental Health Composite International Diagnostic Interview for adolescents. A greater externalizing PGS was associated with a greater odds of any externalizing disorder (OR = 1.29 [1.12, 1.48]; p < 0.01) and ADHD (OR = 1.40 [1.15, 1.70]; p < 0.01) in the whole sample, and in females in particular. There were no main effects of the externalizing PGS on conduct disorder, oppositional defiant disorder, or substance use disorder, nor did adversity exposure moderate these associations. Our results suggest that greater genetic propensity for externalizing disorders is associated with increased odds of any externalizing disorders and ADHD among Mexican adolescents, furthering our understanding of externalizing disorder manifestation in this population.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders.

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.

Mediational pathways between aggregate genetic liability and nonfatal suicide attempt: A Swedish population-based cohort.

Despite recent progress in the genetics of suicidal behavior, the pathway by which genetic liability increases suicide attempt risk is unclear. We investigated the mediational pathways from family/genetic risk for suicide attempt (FGRSSA) to suicide attempt by considering the roles of psychiatric illnesses. In a Swedish cohort, we evaluated time to suicide attempt as a function of FGRSSA and the mediational effects of alcohol use disorder, drug use disorder, attention-deficit/hyperactivity disorder, major depression, anxiety disorder, bipolar disorder, and non-affective psychosis. Analyses were conducted by sex in three age periods: 15-25 years (Nfemales = 850,278 and Nmales = 899,366), 26-35 years (Nfemales = 800,189 and Nmales = 861,774), and 36-45 years (Nfemales = 498,285 and Nmales = 535,831). The association between FGRSSA and suicide attempt was mediated via psychiatric disorders. The highest mediation effects were observed for alcohol use disorder in males (15-25 years, HRtotal = 1.60 [1.59; 1.62], mediation = 14.4%), drug use disorder in females (25-36 years, HRtotal = 1.46 [1.44; 1.49], mediation = 11.2%), and major depression (25-36 years) in females (HRtotal = 1.46 [1.44; 1.49], mediation = 7%) and males (HRtotal = 1.50 [1.47;1.52], mediation = 4.7%). While the direct effect of FGRSSA was higher at ages of 15-25, the mediation via psychiatric disorders was more prominent in later adulthood. Our study informs about the psychiatric illnesses via which genetic liability operates to impact suicide attempt risk, with distinct contributions according to age and sex.

GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice.

G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆9-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.

The Relationship between the Brain-Derived Neurotrophic Factor Gene Polymorphism (Val66Met) and Substance Use Disorder and Relapse.

Substance addiction is a neuropsychiatric disorder characterized by a recurring desire to continue using a substance despite harmful consequences. Brain-derived neurotrophic factor (BDNF) is a protein that plays a role in the activity-dependent remodeling of neural function in adult nervous systems. This study analyzed the association of the rs6265 polymorphism of the BDNF gene in a group of patients addicted to psychoactive substances who were participating in addiction treatment for the first time, in a group of post-relapse psychoactive substance abusers and in a control group. The study also assessed personality and anxiety in all study groups. Statistically significant differences in the frequency of genotypes and alleles were found between all study groups. Compared to the control, both study groups had statistically significantly higher scores for trait and state anxiety. Addicted patients in both groups also had higher scores on the Neuroticism and Openness scales and lower scores on the Extraversion and Agreeableness scales. The results of this study provide further evidence that personality traits, anxiety and the rs6265 polymorphism of the BDNF gene may be risk factors for susceptibility to addiction to psychoactive substances. In addition, they can be a predictor of addiction relapse, but further extensive studies are required to confirm these findings.

The HINT1 Gene rs2526303 Polymorphism and Its Association with Personality Traits in Cigarette Smokers.

The development of a substance use disorder (SUD) is a multifaceted process influenced by both genetic and environmental factors. Recent research has suggested the potential involvement of the HINT1 gene in various aspects of plasticity, mood regulation, anxiety-like behaviour, and stress-coping mechanisms. Moreover, personality traits are also recognised to be instrumental in developing substance dependency. Given these considerations, our study investigated the associations among cigarette smoking, personality traits, and the rs2526303 polymorphism. Additionally, we investigated the interactions between personality traits and rs2526303 in the HINT1 gene. The study group comprised 531 volunteers: 375 cigarette users (mean age = 29.42 ± 10.72; F = 49%, M = 51%) and 156 never-smokers (mean age = 26.93 ± 10.09; F = 79%, M = 21%). Genotyping was conducted using the real-time PCR method, and the NEO Five-Factor Personality Inventory and State-Trait Anxiety Inventory were administered. There were no statistically significant differences in the frequency of rs2526303 genotypes and alleles in the cigarette user group compared to the control group. Compared to the control group, the cigarette users obtained higher scores in the assessment of the NEO-FFI Extraversion scale and lower results for the NEO-FFI Openness, Agreeableness, and Conscientiousness scales. Additionally, there was a statistically significant effect of rs2526303 genotype interaction and cigarette-using status on the conscientiousness scale. These outcomes collectively suggest a notable association between cigarette smoking and specific dimensions of personality, particularly highlighting differences in extraversion, openness, agreeableness, and conscientiousness. Furthermore, the detected interaction effect involving rs2526303 concerning conscientiousness signifies a complex interplay between genetic factors and smoking behaviour.

Parent-child separation and intergenerational transmission of substance use and disorder: Testing across three generations.

There is evidence for intergenerational transmission of substance use and disorder. However, it is unclear whether separation from a parent with substance use disorder (SUD) moderates intergenerational transmission, and no studies have tested this question across three generations. In a three-generation study of families oversampled for familial SUD, we tested whether separation between father (G1; first generation) and child (G2; second generation) moderated the effect of G1 father SUDs on G2 child SUDs. We also tested whether separation between father (G2) and child (G3; third generation) moderated the effect of G2 SUDs on G3 drinking. Finally, we tested whether G1-G2 or G2-G3 separation moderated the mediated effect of G1 SUDs on G3 drinking through G2 SUDs. G1 father-G2 child separation moderated intergenerational transmission. In families with G1-G2 separation, there were no significant effects of father SUD on G2 SUD or G3 drinking. However, in nonseparated families, greater G1 father SUDs predicted heightened G2 SUDs and G3 grandchild drinking. In nonseparated families, G1 father SUDs significantly predicted G2 SUDs, which predicted G3 drinking. However, G2-G3 separation predicted heightened G3 drinking regardless of G2 and G1 SUDs. Parental separation may introduce risk for SUDs and drinking among youth with lower familial risk.

Drug addiction and treatment: An epigenetic perspective.

Drug addiction is a complex disease affected by numerous genetic and environmental factors. Brain regions in reward pathway, neuronal adaptations, genetic and epigenetic interactions causing transcriptional enhancement or repression of multiple genes induce different addiction phenotypes for varying duration. Addictive drug use causes epigenetic alterations and similarly epigenetic changes induced by environment can promote addiction. Epigenetic mechanisms include DNA methylation and post-translational modifications like methylation, acetylation, phosphorylation, ubiquitylation, sumoylation, dopaminylation and crotonylation of histones, and ADP-ribosylation. Non-coding RNAs also induce epigenetic changes. This review discusses these above areas and stresses the need for exploring epidrugs as a treatment alternative and adjunct, considering the limited success of current addiction treatment strategies. Epigenome editing complexes have lately been effective in eukaryotic systems. Targeted DNA cleavage techniques such as CRISPR-Cas9 system, CRISPR-dCas9 complexes, transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs) have been exploited as targeted DNA recognition or anchoring platforms, fused with epigenetic writer or eraser proteins and delivered by transfection or transduction methods. Efficacy of epidrugs is seen in various neuropsychiatric conditions and initial results in addiction treatment involving model organisms are remarkable. Epidrugs present a promising alternative treatment for addiction.

Interactions Between Genetic, Prenatal Substance Use, Puberty, and Parenting are Less Important for Understanding Adolescents' Internalizing, Externalizing, and Substance Use than Developmental Cascades in Multifactorial Models.

This study tested interactions among puberty-related genetic risk, prenatal substance use, harsh discipline, and pubertal timing for the severity and directionality (i.e., differentiation) of externalizing and internalizing problems and adolescent substance use. This is a companion paper to Marceau et al. (2021) which examined the same influences in developmental cascade models. Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 4504 White boys, n = 4287 White girls assessed from the prenatal period through 18.5 years). We hypothesized generally that later predictors would strengthen the influence of puberty-related genetic risk, prenatal substance use exposure, and pubertal risk on psychopathology and substance use (two-way interactions), and that later predictors would strengthen the interactions of earlier influences on psychopathology and substance use (three-way interactions). Interactions were sparse. Although all fourteen interactions showed that later influences can exacerbate or trigger the effects of earlier ones, they often were not in the expected direction. The most robust moderator was parental discipline, and differing and synergistic effects of biological and socially-relevant aspects of puberty were found. In all, the influences examined here operate more robustly in developmental cascades than in interaction with each other for the development of psychopathology and transitions to substance use.

Individual Trajectories of Depressive Symptoms Within Racially-Ethnically Diverse Youth: Associations with Polygenic Risk for Depression and Substance Use Intent and Perceived Harm.

There are distinct individual trajectories of depressive symptoms across adolescence which are most often differentiated into low, moderate/stable, and high/increasing groups. Research has found genetic predisposition for depression associated with trajectories characterized by greater depressive symptoms. However, the majority of this research has been conducted in White youth. Moreover, a separate literature indicates that trajectories with elevated depressive symptoms can result in substance use. It is critical to identify depressive symptom trajectories, genetic predictors, and substance use outcomes in diverse samples in early adolescence to understand distinct processes and convey equitable benefits from research. Using data from the Adolescent Cognitive Brain Development Study (ABCD), we examined parent-reported depressive symptom trajectories within Black/African American (AA, n = 1783), White/European American (EA, n = 6179), and Hispanic/Latinx (LX, n = 2410) youth across four annual assessments in early adolescence (age 9-10 to 12-13). We examined racially/ethnically aligned polygenic scores (Dep-PGS) as predictors of trajectories as well as substance use intent and perceived substance use harm as outcomes at age 12-13. Differential trajectories were found in AA, EA, and LX youth but low and high trajectories were represented within each group. In EA youth, greater Dep-PGS were broadly associated with membership in trajectories with greater depressive symptoms. Genetic effects were not significant in AA and LX youth. In AA youth, membership in the low trajectory was associated with greater substance use intent. In EA youth, membership in trajectories with higher depressive symptoms was associated with greater substance use intent and less perceived harm. There were no associations between trajectories and substance use intent and perceived harm in LX youth. These findings indicate that there are distinct depressive symptom trajectories in AA, EA, and LX youth, accompanied by unique associations with genetic predisposition for depressive symptoms and substance use outcomes.

USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder.

The risk of developing drug addiction is strongly influenced by the epigenetic landscape and chromatin remodeling. While histone modifications such as methylation and acetylation have been studied in the ventral tegmental area and nucleus accumbens (NAc), the role of H2A monoubiquitination remains unknown. Our investigations, initially focused on the scaffold protein melanoma-associated antigen D1 (Maged1), reveal that H2A monoubiquitination in the paraventricular thalamus (PVT) significantly contributes to cocaine-adaptive behaviors and transcriptional repression induced by cocaine. Chronic cocaine use increases H2A monoubiquitination, regulated by Maged1 and its partner USP7. Accordingly, Maged1 specific inactivation in thalamic Vglut2 neurons, or USP7 inhibition, blocks cocaine-evoked H2A monoubiquitination and cocaine locomotor sensitization. Additionally, genetic variations in MAGED1 and USP7 are linked to altered susceptibility to cocaine addiction and cocaine-associated symptoms in humans. These findings unveil an epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factors for drug addiction in humans.