The Influence of Genetic Polymorphic Variability of the Catechol-O-methyltransferase Gene in a Group of Patients with a Diagnosis of Behavioural Addiction, including Personality Traits.

Gambling Disorder (GD) is characterised by a harmful, enduring, and recurrent involvement in betting-related behaviours. Therefore, GD shares similar biological mechanisms and symptoms to substance use disorders (SUD). Therefore, in this study, we chose the behavioural addictions group. During the examination and recruitment to the study, it turned out that all the people undergoing treatment for gambling addiction were also addicted to amphetamines, which is consistent with the biological mechanism related to cerebral neurotransmission. The aim of the study was to investigate the association of the COMT gene polymorphism with behavioral addiction. The study group consisted of 307 participants: 107 men with gambling disorder and amphetamine dependency (mean age = 27.51, SD = 5.25) and 200 non-addicted, nor dependent, free from neuro-psychiatric disorders control group men (mean age = 20.20, SD = 4.51). Both groups were subjected to psychometric evaluation using the State-Trait Anxiety Inventory and the NEO Five-Factor Personality Inventory. Genomic DNA was extracted from venous blood following standard protocols. Determination of the rs4680 polymorphism in the COMT gene was performed using the real-time PCR technique. Statistically significant differences in the frequency of rs4680 genotypes were found in the tested sample of subjects compared with the control group (p = 0.03543). Subjects with gambling disorder and amphetamine use disorder compared to the control group obtained higher scores in the assessment of the STAI trait scale (p = 0.0019), state scale (p < 0.0000), and NEO-FFI Neuroticism scale (p < 0.0000). Significantly lower results were obtained for the NEO-FFI Agreeability scale (p < 0.0000). Additionally, a significant statistical impact of gambling disorder and amphetamine use disorder, and the COMT rs4680 genotype was demonstrated for the score of the STAI trait (p = 0.0351) and state (p = 0.0343) and the NEO-FFI Conscientiousness scale (p = 0.0018). We conclude that COMT and its polymorphic variant influence the development of addiction. Still, considering its multifactorial and polygenic nature, it should be combined with other factors such as personality.

Early developmental risks for tobacco addiction: A probabilistic epigenesis framework.

Considerable progress has been made in elucidating the relationships between early life psychobiological and environmental risk factors and the development of tobacco addiction. However, a comprehensive understanding of the heterogeneity in tobacco addiction phenotypes requires integrating research findings. The probabilistic epigenesis meta-theory offers a valuable framework for this integration, considering systemic, multilevel, developmental, and evolutionary perspectives. In this paper, we critically review relevant research on early developmental risks associated with tobacco addiction and highlight the integrative heuristic value of the probabilistic epigenesis framework for this research. For this, we propose a four-level systems approach as an initial step towards integration, analyzing complex interactions among different levels of influence. Additionally, we explore a coaction approach to examine key interactions between early risk factors. Moreover, we introduce developmental pathways to understand interindividual differences in tobacco addiction risk during development. This integrative approach holds promise for advancing our understanding of tobacco addiction etiology and informing potentially effective intervention strategies.

Causal relationship between addictive behaviors and epilepsy risk: A mendelian randomization study.

BACKGROUND: Previous studies have reported inconsistent results regarding the potential relationships between addictive behaviors and the risk of epilepsy. OBJECTIVE: To assess whether genetically predicted addictive behaviors are causally associated with the risk of epilepsy outcomes. METHODS: The causation between five addictive behaviors (including cigarettes per day, alcoholic drinks per week, tea intake, coffee intake, and lifetime cannabis use) and epilepsy was evaluated by using a two-sample Mendelian Randomization (MR) analysis. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (MR Egger, weighted median, simulation extrapolation corrected MR-Egger, and Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO)) were performed to complement IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. RESULTS: The IVW analysis method indicated an approximately 20% increased risk of epilepsy per standard deviation increase in lifetime cannabis use (odds ratio [OR], 1.20; 95% confidence interval [CI]), 1.02-1.42, P = 0.028). However, there is no causal association between the other four addictive behaviors and the risk of epilepsy (cigarettes per day: OR, 1.04; 95% CI, 0.92-1.18, P = 0.53; alcoholic drinks per week: OR, 1.31; 95% CI, 0.93-1.84, P = 0.13; tea intake: OR, 1.15; 95% CI, 0.84-1.56, P = 0.39; coffee intake: OR, 0.86; 95% CI, 0.59-1.23, P = 0.41). The other MR analysis methods and further leave-one-out sensitivity analysis suggested the results were robust. CONCLUSION: This MR study indicated a potential genetically predicted causal association between lifetime cannabis use and higher risk of epilepsy. As for the other four addictive behaviors, no evidence of a causal relationship with the risk of epilepsy was found in this study.

The Stage-Based Model of Addiction-Using Drosophila to Investigate Alcohol and Psychostimulant Responses.

Addiction is a progressive and complex disease that encompasses a wide range of disorders and symptoms, including substance use disorder (SUD), for which there are few therapeutic treatments. SUD is the uncontrolled and chronic use of substances despite the negative consequences resulting from this use. The progressive nature of addiction is organized into a testable framework, the neurobiological stage-based model, that includes three behavioral stages: (1) binge/intoxication, (2) withdrawal/negative affect, and (3) preoccupation/anticipation. Human studies offer limited opportunities for mechanistic insights into these; therefore, model organisms, like Drosophila melanogaster, are necessary for understanding SUD. Drosophila is a powerful model organism that displays a variety of SUD-like behaviors consistent with human and mammalian substance use, making flies a great candidate to study mechanisms of behavior. Additionally, there are an abundance of genetic tools like the GAL4/UAS and CRISPR/Cas9 systems that can be used to gain insight into the molecular mechanisms underlying the endophenotypes of the three-stage model. This review uses the three-stage framework and discusses how easily testable endophenotypes have been examined with experiments using Drosophila, and it outlines their potential for investigating other endophenotypes.

The first genome-wide association study of internet addiction; Revealed substantial shared risk factors with neurodevelopmental psychiatric disorders.

BACKGROUND: Internet addiction disorder (IAD) is listed as a disorder requiring further studies in the diagnostic and statistical manual of mental disorders (DSM-V). Psychological studies showed significant co-morbidity of IAD with depression, alcohol abuse, and anxiety disorder. Etiology and genetic bases of IAD are unclear. AIMS: Present study aimed to investigate the genetic, psychological, and cognitive bases of a tendency to internet addiction. METHODS AND PROCEDURES: DNA was extracted from blood samples of IADs (N = 16,520) and 18,000 matched non-psychiatric subjects. Genotyping for the subjects was performed using SNP Array. Psychological, neuropsychological, and neurological characteristics were conducted. OUTCOMES AND RESULTS: Seventy-two SNPs in 24 genes have been detected significantly associated with IAD. Most of these SNPs were risk factors for psychiatric disorders. Most similarity detected with autism spectrum disorder, bipolar disorder and schizophrenia. Higher anxiety, stress, and neuroticism and deficits in working memory, attention, planning, and processing speed were detected in IADs. CONCLUSIONS: This study is the first genome-wide association study of IAD that showed strong shared genetic bases with neurodevelopmental disabilities and psychiatric disorders. IMPLICATIONS: Genetic risk factors in IADs may cause several cognitive and neurodevelopmental brain function abnormalities, which lead to excessive Internet usage. It may suggest that IAD could be a marker for vulnerability to developmental psychiatric disorders.

The Genetically Informed Neurobiology of Addiction (GINA) model.

Addictions are heritable and unfold dynamically across the lifespan. One prominent neurobiological theory proposes that substance-induced changes in neural circuitry promote the progression of addiction. Genome-wide association studies have begun to characterize the polygenic architecture undergirding addiction liability and revealed that genetic loci associated with risk can be divided into those associated with a general broad-spectrum liability to addiction and those associated with drug-specific addiction risk. In this Perspective, we integrate these genomic findings with our current understanding of the neurobiology of addiction to propose a new Genetically Informed Neurobiology of Addiction (GINA) model.

Pharmacogenetics of Addiction Therapy.

Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies with response to treatment based on individual genetic makeup. In this chapter, we will discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The continued elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.

Why haven't we solved the addiction crisis?

The current addiction crisis has destroyed a multitude of lives, leaving millions of fatalities worldwide in its wake. At the same time, various governmental agencies dedicated to solving this seemingly never-ending dilemma have not yet succeeded or delivered on their promises. We understand that addictive behavioral seeking is a multi-faceted neurobiological and spiritually complicated phenomenon. However, although the substitution replacement approach, especially to treat Opioid Use Disorder (OUD), has importance for harm reduction in the short term, it does not bring about a harm-free recovery or prevention. Instead, we propose a promising novel approach that uses genetic risk testing with induction of dopamine homeostasis and an objective Brain Health Check during youth. Our model involves a six-hit approach known as the "Reward Dysregulation Syndrome Solution System," which can identify addiction risk and target the root cause of addiction, dopamine dysregulation. While we applaud all past sophisticated neurogenetic and neuropharmacological research, our opinion is that in the long term, addiction scientists and clinicians might characterize preaddiction using tests; for example, administering the validated RDSQuestionarre29, genetic risk assessment, a modified brain health check, or diagnostic framing of mild to moderate Substance Use Disorder (SUD). The preaddiction concept could incentivize the development of interventions to prevent addiction from developing in the first place and target and treat neurotransmitter imbalances and other early indications of addiction. WC 222.

MicroRNAs in drug addiction: Current status and future perspectives.

Drug addiction is a chronic and relapsing brain disorder characterized by compulsive drug seeking and continued drug use despite adverse consequences. The high prevalence and social burden of addiction is indisputable; however, the available intervention is insufficient. Abnormal gene expression is observed in reward-related brain regions in animal models of addiction. The modulation of gene expression and aberrant adaptation of neural networks attribute to the changes in brain function under repeated exposure to addictive drugs. The emerging recognition of the role of microRNA (miRNA) provides new insights into many biological and pathological processes in the central nervous system. Considerable studies have demonstrated that miRNAs are strong modulators of posttranscriptional gene expression in drug addiction. Here, we provide an overview of miRNAs, followed by evidence for aberrant miRNA expression and regulatory roles of miRNAs in drug addiction as well as neuroadaptation. We concluded by providing our perspectives that miRNAs have the potential as novel therapeutic targets for drug addiction.

Chromatin architecture in addiction circuitry identifies risk genes and potential biological mechanisms underlying cigarette smoking and alcohol use traits.

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and newly generated midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ~26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture helps refine neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.

Association of the dopamine D2 receptor rs1800497 polymorphism with food addiction, food reinforcement, and eating behavior in Chilean adults.

PURPOSE: The regulation of food intake and body weight involves two interacting systems: (a) The homeostatic system (including biological regulators of hunger and satiety) and (b) the non-homeostatic system, (involving concepts of food reinforcement and food addiction). Studies have established a strong genetic component in eating behavior and obesity. The TaqI A1 polymorphism (rs1800497) has previously been associated with eating behavior, diminished dopamine D2 receptor (DRD2) density, higher body mass, and food reinforcement, but relations to food addiction remain unclear. AIM: To evaluate the association between the polymorphism rs1800497 with eating behavior, food reinforcement and food addiction in Chilean adults. METHODS: This cross-sectional study recruited a convenience sample of 97 obese, 25 overweight and 99 normal-weight adults (18-35 years). Anthropometric measurements were performed by standard procedures. Eating behavior was assessed using the: Yale Food Addiction Scale (YFAS), the Three Factor Eating Behavior Questionnaire and the Food Reinforcement Value Questionnaire (FRVQ). The DRD2 genotype (rs1800497) was determined by taqman assays. RESULTS: Twenty-two percentage of the participants met the criteria for food addiction. Food addiction was higher in women than men (26% vs 10.7%) and in obese compared to non-obese (40% vs 6%). There was no relationship between food addiction and DRD2 genotype. However when stratified by sex and nutritional status, obese female carriers of the A1 allele reported greater scores on emotional eating and snack food reinforcement compared to non-carriers. CONCLUSIONS: The DRD2 polymorphism is associated with some hedonic aspects of eating behavior, namely food reinforcement and emotional eating but not food addiction, and this association may be moderated by sex and obesity status, with obese women who are carriers of this genetic variant at higher risk. LEVEL OF EVIDENCE: Level V: evidence obtained from a cross-sectional descriptive study.

Genes identified in rodent studies of alcohol intake are enriched for heritability of human substance use.

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.

Chromatin-mediated alternative splicing regulates cocaine-reward behavior.

Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.

Effects of sex and genotype in human APOE-targeted replacement mice on alcohol self-administration measured with the automated IntelliCage system before and after repeated mild traumatic brain injury.

BACKGROUND: Few studies have examined the association between APOE genotype and alcohol use. Although some of these studies have reported outcomes associated with a history of drinking, none have examined alcohol-seeking behavior. In addition, no preclinical studies have examined alcohol use as a function of APOE genotype with or without traumatic brain injury. METHODS: Male and female human APOE3- and APOE4-targeted replacement (TR) mice were used to assess voluntary alcohol seeking longitudinally using a 2-bottle choice paradigm conducted within the automated IntelliCage system prior to and following repeated mild TBI (rmTBI). Following an acquisition phase in which the concentration of ethanol (EtOH) was increased to 12%, a variety of drinking paradigms that included extended alcohol access (EAA1 and EAA2), alcohol deprivation effect (ADE), limited access drinking in the dark (DID), and progressive ratio (PR) were used to assess alcohol-seeking behavior. Additional behavioral tasks were performed to measure cognitive function and anxiety-like behavior. RESULTS: All groups readily consumed increasing concentrations of EtOH (4-12%) during the acquisition phase. During the EAA1 period (12% EtOH), there was a significant genotype effect in both males and females for EtOH preference. Following a 3-week abstinence period, mice received sham or rmTBI resulting in a genotype- and sex-independent main effect of rmTBI on the recovery of righting reflex and a main effect of rmTBI on spontaneous home-cage activity in females only. Reintroduction of 12% EtOH (EAA2) resulted in a significant effect genotype for alcohol preference in males with APOE4 mice displaying increased preference and motivation for alcohol compared with APOE3 mice independent of TBI while in females, there was a significant genotype × TBI interaction under the ADE and DID paradigms. Finally, there was a main effect of rmTBI on increased risk-seeking behavior in both sexes, but no effect on spatial learning or cognitive flexibility. CONCLUSION: These results suggest that sex and APOE genotype play a significant role in alcohol consumption and may subsequently influence long-term recovery following traumatic brain insults.

Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction.

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates.

Addiction-Associated Genetic Variants Implicate Brain Cell Type- and Region-Specific Cis-Regulatory Elements in Addiction Neurobiology.

Recent large genome-wide association studies have identified multiple confident risk loci linked to addiction-associated behavioral traits. Most genetic variants linked to addiction-associated traits lie in noncoding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied stratified linkage disequilibrium score regression to compare genome-wide association studies to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative CREs marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of female and male mouse neuronal subtypes: cortical excitatory, D1, D2, and PV. Last, we developed machine learning models to predict mouse cell type-specific open chromatin, enabling us to further categorize human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuronal subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.SIGNIFICANCE STATEMENT We combine statistical genetic and machine learning techniques to find that the predisposition to for nicotine, alcohol, and cannabis use behaviors can be partially explained by genetic variants in conserved regulatory elements within specific brain regions and neuronal subtypes of the reward system. Our computational framework can flexibly integrate open chromatin data across species to screen for putative causal variants in a cell type- and tissue-specific manner for numerous complex traits.

[An associations of possible genetic risk markers for Internet addiction with childhood trauma experience and personality traits in young adults : preliminary results]. / Svyaz' geneticheskikh markerov riska razvitiya internet-zavisimosti s detskim psikhotravmiruyushchim opytom i lichnostnymi osobennostyami u molodykh vzroslykh: predvaritel'nye rezul'taty.

OBJECTIVE: To study was to test an associations of the preliminary genetic risk markers for Internet addiction (IA) with clinical, psychological and personality characteristics, taking into account the childhood traumatic experience, in 44 IA persons compared with 120 healthy individuals. MATERIAL AND METHODS: The study included 164 participants: 44 individuals with IZ (group IZ), male and female, aged 16 to 30 years in the absence of diagnoses of mental health problems. diseases from rubrics F00-09 and F20-29 (ICD-10) and 120 healthy (control group). RESULTS AND CONCLUSION: We have found an associations of the preliminary IA genetic risk markers with some personality traits and behavioral characteristics (TCI-125, TIPI) and with the childhood trauma experience (ACE IQ, CTQ), both for healthy individuals and to a greater extent for IA individuals, that may suggests the possible effects of the gene-environment interaction on a risk of developing IA. The data obtained on the structure of associations between IA genetic risk markers and individual psychological characteristics under the significant influence of the childhood trauma experience allow us to proceed with the construction of models for IA risk prediction taking into account the "gene - environment" interactions.