Investigating the role of nicotinic acetylcholine receptors in menthol's effects in mice.

The use of menthol in tobacco products has been linked to an increased likelihood of developing nicotine dependence. The widespread use of menthol can be attributed to its unique sensory characteristics; however, emerging evidence suggests that menthol also alters sensitivity to nicotine through modulation of nicotinic acetylcholine receptors (nAChRs). Nicotinic subunits, such as ß2 and α5, are of interest due to their implications in nicotine reward, reinforcement, intake regulation, and aversion. This study, therefore, examined the in vivo relevance of ß2 and α5 nicotinic subunits on the pharmacological and behavioral effects of menthol. Data suggests that the α5 nicotinic subunit modulates menthol intake in mice. Overall, deletion or a reduction in function of the α5 subunit lessened aversion to menthol. α5 KO mice and mice possessing the humanized α5 SNP, a variant that confers a nicotine dependence phenotype in humans, demonstrated increased menthol intake compared to their WT counterparts and in a sex-related fashion for α5 SNP mice. We further reported that the modulatory effects of the α5 subunit do not extend to other aversive tastants like quinine, suggesting that deficits in α5* nAChR signaling may not abolish general sensitivity to the aversive effects of other noxious chemicals. Further probing into the role of α5 in other pharmacological properties of menthol revealed that the α5 subunit does not modulate the antinociceptive properties of menthol in mice and suggests that the in vivo differences observed are likely not due to the direct effects of menthol on α5-containing nAChRs in vitro.

Nicotine use disorder and Neuregulin 3: Opportunities for precision medicine.

Nicotine use disorder remains a major public health emergency despite years of trumpeting the consequences of smoking. This is likely due to the complex interplay of genetics and nicotine exposure across the lifespan of these individuals. Genetics influence all aspects of life, including complex disorders such as nicotine use disorder. This review first highlights the critical neurocircuitry underlying nicotine dependence and withdrawal, and then describes the cellular signaling mechanisms involved. Finally, current genetic, genomic, and transcriptomic evidence for new drug development of smoking cessation aids is discussed, with a focus on the Neuregulin 3 Signaling Pathway.

Nicotine Motivated Behavior in C. elegans.

To maximize the advantages offered by Caenorhabditis elegans as a high-throughput (HTP) model for nicotine dependence studies, utilizing its well-defined neuroconnectome as a robust platform, and to unravel the genetic basis of nicotine-motivated behaviors, we established the nicotine conditioned cue preference (CCP) paradigm. Nicotine CCP enables the assessment of nicotine preference and seeking, revealing a parallel to fundamental aspects of nicotine-dependent behaviors observed in mammals. We demonstrated that nicotine-elicited cue preference in worms is mediated by nicotinic acetylcholine receptors and requires dopamine for CCP development. Subsequently, we pinpointed nAChR subunits associated with nicotine preference and validated human GWAS candidates linked to nicotine dependence involved in nAChRs. Functional validation involves assessing the loss-of-function strain of the CACNA2D3 ortholog and the knock-out (KO) strain of the CACNA2D2 ortholog, closely related to CACNA2D3 and sharing human smoking phenotypes. Our orthogonal approach substantiates the functional conservation of the α2δ subunit of the calcium channel in nicotine-motivated behavior. Nicotine CCP in C. elegans serves as a potent affirmation of the cross-species functional relevance of GWAS candidate genes involved in nicotine seeking associated with tobacco abuse, providing a streamlined yet comprehensive system for investigating intricate behavioral paradigms within a simplified and reliable framework.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation.

INTRODUCTION: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. METHODS: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). RESULTS: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. DISCUSSION: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

Polygenic scores for tobacco use provide insights into systemic health risks in a diverse EHR-linked biobank in Los Angeles.

Tobacco use is a major risk factor for many diseases and is heavily influenced by environmental factors with significant underlying genetic contributions. Here, we evaluated the predictive performance, risk stratification, and potential systemic health effects of tobacco use disorder (TUD) predisposing germline variants using a European- ancestry-derived polygenic score (PGS) in 24,202 participants from the multi-ancestry, hospital-based UCLA ATLAS biobank. Among genetically inferred ancestry groups (GIAs), TUD-PGS was significantly associated with TUD in European American (EA) (OR: 1.20, CI: [1.16, 1.24]), Hispanic/Latin American (HL) (OR:1.19, CI: [1.11, 1.28]), and East Asian American (EAA) (OR: 1.18, CI: [1.06, 1.31]) GIAs but not in African American (AA) GIA (OR: 1.04, CI: [0.93, 1.17]). Similarly, TUD-PGS offered strong risk stratification across PGS quantiles in EA and HL GIAs and inconsistently in EAA and AA GIAs. In a cross-ancestry phenome-wide association meta-analysis, TUD-PGS was associated with cardiometabolic, respiratory, and psychiatric phecodes (17 phecodes at P < 2.7E-05). In individuals with no history of smoking, the top TUD-PGS associations with obesity and alcohol-related disorders (P = 3.54E-07, 1.61E-06) persist. Mendelian Randomization (MR) analysis provides evidence of a causal association between adiposity measures and tobacco use. Inconsistent predictive performance of the TUD-PGS across GIAs motivates the inclusion of multiple ancestry populations at all levels of genetic research of tobacco use for equitable clinical translation of TUD-PGS. Phenome associations suggest that TUD-predisposed individuals may require comprehensive tobacco use prevention and management approaches to address underlying addictive tendencies.

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.

Epigenetic mechanisms of nicotine dependence.

Smoking continues to be a leading cause of preventable disease and death worldwide. Nicotine dependence generates a lifelong propensity towards cravings and relapse, presenting an ongoing challenge for the development of treatments. Accumulating evidence supports a role for epigenetics in the development and maintenance of addiction to many drugs of abuse, however, the involvement of epigenetics in nicotine dependence is less clear. Here we review evidence that nicotine interacts with epigenetic mechanisms to enable the maintenance of nicotine-seeking across time. Research across species suggests that nicotine increases permissive histone acetylation, decreases repressive histone methylation, and modulates levels of DNA methylation and noncoding RNA expression throughout the brain. These changes are linked to the promoter regions of genes critical for learning and memory, reward processing and addiction. Pharmacological manipulation of enzymes that catalyze core epigenetic modifications regulate nicotine reward and associative learning, demonstrating a functional role of epigenetic modifications in nicotine dependence. These findings are consistent with nicotine promoting an overall permissive chromatin state at genes important for learning, memory and reward. By exploring these links through next-generation sequencing technologies, epigenetics provides a promising avenue for future interventions to treat nicotine dependence.

Association of nicotine dependence and gut microbiota: a bidirectional two-sample Mendelian randomization study.

Background: Nicotine dependence is a key factor influencing the diversity of gut microbiota, and targeting gut microbiota may become a new approach for the prevention and treatment of nicotine dependence. However, the causal relationship between the two is still unclear. This study aims to investigate the causal relationship between nicotine dependence and gut microbiota. Methods: A two-sample bidirectional Mendelian randomization (MR) study was conducted using the largest existing gut microbiota and nicotine dependence genome-wide association studies (GWAS). Causal relationships between genetically predicted nicotine dependence and gut microbiota abundance were examined using inverse variance weighted, MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO approaches. Cochrane's Q test, MR-Egger intercept test, and leave-one-out analysis were performed as sensitivity analyses to assess the robustness of the results. Multivariable Mendelian randomization analysis was also conducted to eliminate the interference of smoking-related phenotypes. Reverse Mendelian randomization analysis was then performed to determine the causal relationship between genetically predicted gut microbiota abundance and nicotine dependence. Results: Genetically predicted nicotine dependence had a causal effect on Christensenellaceae (ß: -0.52, 95% CI: -0.934-0.106, P = 0.014). The Eubacterium xylanophilum group (OR: 1.106, 95% CI: 1.004-1.218), Lachnoclostridium (OR: 1.118, 95% CI: 1.001-1.249) and Holdemania (OR: 1.08, 95% CI: 1.001-1.167) were risk factors for nicotine dependence. Peptostreptococcaceae (OR: 0.905, 95% CI: 0.837-0.977), Desulfovibrio (OR: 0.014, 95% CI: 0.819-0.977), Dorea (OR: 0.841, 95% CI. 0.731-0.968), Faecalibacterium (OR: 0.831, 95% CI: 0.735-0.939) and Sutterella (OR: 0.838, 95% CI: 0.739-0.951) were protective factor for nicotine dependence. The sensitivity analysis showed consistent results. Conclusion: The Mendelian randomization study confirmed the causal link between genetically predicted risk of nicotine dependence and genetically predicted abundance of gut microbiota. Gut microbiota may serve as a biomarker and offer insights for addressing nicotine dependence.

Biochemical and genetic biomarkers associated with nicotine dependence in Mexican smokers.

Cigarette smoking remains an important health concern and is still a leading cause of preventable mortality. Nicotine is the substance responsible for sustained tobacco use and dependence. Identification of biomarkers underlying nicotine dependence behavior is important to identify people at risk for this dependence. In the present study, we identified biochemical and genetic biomarkers of nicotine dependence detected by the Fagerström Test for Nicotine Dependence (FTDN) in Mexican smokers. The nicotine metabolites nicotine-N'-oxide, trans-3'-hydroxycotinine-glucuronide (3HC-O-Gluc), and nicotine-N-Gluc (Gluc) were useful to differentiate nicotine-dependent from non-dependent subjects (p < .0001) with an area under the curve (AUC) of 0.7818. Genetic variants in CYP2A6, FMO3, and UGT2B7 (rs2431413, rs28363545, and rs7439326, respectively) were associated with nicotine dependence (p = .03, p = .01, p = .01, respectively). Variations in the enzymatic activity of CYP2A6 were associated with altered nicotine-N'-oxide and 3HC-O-Gluc levels. Decreased urinary levels of 3HC-O-Gluc and increased nicotine-N'-oxide were associated with a decrease in the functional activity of CYP2A6. A strong positive correlation was observed between the ratio of urinary 3HC/cotinine, a measure of CYP2A6 activity, and the levels of 3HC-O-Gluc (p < .0001, r = .6835), while a strong negative correlation was observed with nicotine-N'-oxide (p < .0001, r = .6522) in nicotine-dependent subjects. No correlations were observed in non-nicotine-dependent subjects. These data suggest that particular urinary nicotine metabolites and genetic variants involved in nicotine metabolism are useful to identify subjects with nicotine dependence in the Mexican population.

An in-depth association analysis of genetic variants within nicotine-related loci: Meeting in middle of GWAS and genetic fine-mapping.

In the last two decades of Genome-wide association studies (GWAS), nicotine-dependence-related genetic loci (e.g., nicotinic acetylcholine receptor - nAChR subunit genes) are among the most replicable genetic findings. Although GWAS results have reported tens of thousands of SNPs within these loci, further analysis (e.g., fine-mapping) is required to identify the causal variants. However, it is computationally challenging for existing fine-mapping methods to reliably identify causal variants from thousands of candidate SNPs based on the posterior inclusion probability. To address this challenge, we propose a new method to select SNPs by jointly modeling the SNP-wise inference results and the underlying structured network patterns of the linkage disequilibrium (LD) matrix. We use adaptive dense subgraph extraction method to recognize the latent network patterns of the LD matrix and then apply group LASSO to select causal variant candidates. We applied this new method to the UK biobank data to identify the causal variant candidates for nicotine addiction. Eighty-one nicotine addiction-related SNPs (i.e.,-log(p) > 50) of nAChR were selected, which are highly correlated (average r2>0.8) although they are physically distant (e.g., >200 kilobase away) and from various genes. These findings revealed that distant SNPs from different genes can show higher LD r2 than their neighboring SNPs, and jointly contribute to a complex trait like nicotine addiction.

The role of miRNA-144-3p/Oprk1/KOR in nicotine dependence and nicotine withdrawal in male rats.

INTRODUCTION: The kappa-opioid receptor (KOR) has been implicated in mediating the behavioral and biochemical effects associated with nicotine reward and withdrawal; however, its underlying mechanisms remain to be further explored. METHODS: Adult male Sprague-Dawley rats were used to establish a nicotine dependence and withdrawal model by injecting nicotine (3 mg/kg/day, s.c.) or vehicle for 14 days, followed by the termination of nicotine for 7 days. Body weight gain, pain behaviors, and withdrawal scores were assessed in succession. MicroRNA (miRNA) sequencing was performed, and quantitative real-time PCR was used to detect the expression of candidate miRNAs and Oprk1. Western blotting was performed to examine KOR protein expression of KOR. Luciferase assay was conducted to validate the relationship of certain miRNAs/Oprk1. RESULTS: The behavioral results showed that nicotine dependence and withdrawal induced behavioral changes. Biochemical analyses demonstrated that miR-144-3p expression decreased and Oprk1/KOR expression increased in the prefrontal cortex, nucleus accumben, and hippocampus. Further investigation suggested that miR-144-3p exerted an inhibitory effect on Oprk1 expression in PC12 cells. CONCLUSIONS: This study revealed that miR-144-3p/Oprk1/KOR might be a potential pathway underlying the adverse effects induced by nicotine dependence and withdrawal, and might provide a novel therapeutic target for smoking cessation. IMPLICATIONS: This study demonstrates an impact of nicotine dependence and nicotine withdrawal on behavioral outcomes and the expressions of miR-144-3p/Oprk1/KOR in male rats. These findings have important translational implications given the continued use of nicotine and the difficulty in smoking cessation worldwide, which can be applied to alleviated the adverse effects induced by nicotine dependence and withdrawal, thus assist smokers to quit smoking.

Rare coding variants in CHRNB2 reduce the likelihood of smoking.

Human genetic studies of smoking behavior have been thus far largely limited to common variants. Studying rare coding variants has the potential to identify drug targets. We performed an exome-wide association study of smoking phenotypes in up to 749,459 individuals and discovered a protective association in CHRNB2, encoding the ß2 subunit of the α4ß2 nicotine acetylcholine receptor. Rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking heavily (odds ratio (OR) = 0.65, confidence interval (CI) = 0.56-0.76, P = 1.9 × 10-8). An independent common variant association in the protective direction ( rs2072659 ; OR = 0.96; CI = 0.94-0.98; P = 5.3 × 10-6) was also evident, suggesting an allelic series. Our findings in humans align with decades-old experimental observations in mice that ß2 loss abolishes nicotine-mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.

Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Dissecting the epigenomic differences between smoking and nicotine dependence in a veteran cohort.

Smoking is a serious public health issue linked to more than 8 million deaths per year worldwide and may lead to nicotine dependence (ND). Although the epigenomic literature on smoking is well established, studies evaluating the role of epigenetics in ND are limited. In this study, we examined the epigenomic signatures of ND and how these differ from smoking exposure to identify biomarkers specific to ND. We investigated the peripheral epigenetic profile of smoking status (SS) and ND in a US male veteran cohort. DNA from saliva was collected from 1135 European American (EA) male US military veterans. DNAm was assessed using the Illumina Infinium Human MethylationEPIC BeadChip array. SS was evaluated as current smokers (n = 137; 12.1%) and non-current smokers (never and former; n = 998; 87.9%). NDFTND was assessed as a continuous variable using the Fagerström Test for ND (FTND; n = 1135; mean = 2.54 ± 2.29). Epigenome-wide association studies (EWAS) and co-methylation analyses were conducted for SS and NDFTND . A total of 450 and 22 genome-wide significant differentially methylated sites (DMS) were associated with SS and NDFTND , respectively (15 overlapped DMS). We identified 97 DMS (43 genes) in SS-EWAS previously reported in the literature, including AHRR and F2RL3 genes (p-value: 1.95 × 10-83 to 4.55 × 10-33 ). NDFTND novel DMS mapped to NEUROG1, ANPEP, and SLC29A1. Co-methylation analysis identified 386 modules (11 SS-related and 19 NDFTND -related). SS-related modules showed enrichment for alcoholism, while NDFTND -related modules were enriched for nicotine addiction. This study confirms previous findings associated with SS and identifies novel and-potentially specific-epigenetic biomarkers of ND that may inform prognosis and novel treatment strategies.

Advice for smokers in smoking cessation clinic: a review.

Background: Tobacco dependence has become a global public health concern. We chose to investigate the modifiable factors and motivations during the period of smoking cessation based on the mechanism of nicotine addiction. Methods: We selected emotion, sleep, alcohol, caffeine beverages, mental activities after dinner, exercise and CYP2A6 genotype as influencing factors, and provided corresponding recommendations for smokers based on these factors. Based on these characteristics, we reviewed literature and summarized the relationship between these factors and nicotine dependence or smoking. Results: Different emotion, sleep deficiency, caffeine intake, alcohol consumption, mental activities after dinner, physical exercises and CYP2A6 genotype have an effect on daily smoking and nicotine dependence. Conclusion: These suggestions related literature-derived factors may increase the success rate of smoking cessation.

Adiponectin. rs266729 Polymorphism and Nicotine Dependence Interaction: Genetic Investigations on the Anxiety Susceptibility.

BACKGROUND AND AIMS: Nicotine dependence (ND)-induced anxiety might be modulated by genetic polymorphisms. The gene-by-environment interaction can be fitted into the diathesis-stress and differential susceptibility models. Nevertheless, knowledge of the interaction between adiponectin (ADPN) polymorphisms and ND on the incident mental disorder is currently scarce. This study aims to understand the role of ADPN rs266729 on anxiety in patients with ND while elucidating the psychology model and the various reactions across genotypes. METHODS: We included 315 Chinese males with confirmed ND, measured using the Fagerstrom test for nicotine dependence (FTND). Anxiety was assessed using the Self-rating Anxiety Scale. Genomic DNA was extracted and genotyped from peripheral blood. Hierarchical regression models were used to test the interactions. RESULTS: There was a significant interaction between ADPN rs266729 and ND (ß = -0.19, p < 0.05). The CC homozygote was more likely to be affected by ND-induced anxiety (ß = 0.14, t = 4.43, p < 0.01). Re-parameterized regression models revealed that the interaction between ADPN rs266729 and ND could fit the strong differential susceptibility model (R2 = 0.05, p < 0.001). CONCLUSIONS: ADPN rs266729 was correlated with susceptibility to anxiety symptoms among male adults with ND and could fit the differential susceptibility model. The CC homozygote of rs266729 was a plasticity factor that increased anxiety symptoms in individuals with ND.

Genetic differences in nicotine sensitivity and metabolism in C57BL/6J and NOD/ShiLtJ mouse strains.

Genetic background impacts sensitivity to nicotine's rewarding and aversive effects and metabolism, which influences susceptibility to nicotine addiction. This is important because sensitivity to nicotine influences susceptibility to nicotine addiction. Thus, understanding genetic contribution to nicotine sensitivity can aid in identifying risk factors for nicotine addiction. Genetic variability in addiction phenotypes can be modeled in rodent systems, and comparisons of nicotine sensitivity in inbred mice can identify contributing genetic substrates. Our laboratory has identified differences in nicotine sensitivity in male mice from two inbred mouse strains, C57BL/6J and NOD/ShiLtJ. We found that the NOD/ShiLtJ strain experienced greater nicotine-induced locomotor depression and hypothermia than the C57BL/6J strain. To investigate possible differences in nicotine metabolism between strains, subjects were treated with acute nicotine and serum and urine samples were analyzed using LC-MS/MS to quantify nicotine and metabolites. This analysis revealed that NOD/ShiLtJ mice had similar serum nicotine but lower cotinine and 3'-hydroxycotinine levels after nicotine treatment when compared to C57BL/6J mice. Possible genetic factors mediating strain differences were identified by surveying nicotine sensitivity- and metabolism-related genes within the Mouse Phenome Database SNP retrieval tool. Polymorphisms were found in 15 of the 26 examined gene sequences. Liver expression levels of nicotine metabolism-related genes (Cyp2a5, Cyp2a4, and Aox1) were measured using qPCR. NOD/ShiLtJ mice showed lower expression of Cyp2a5 and Cyp2a4 and greater expression of Aox1 in liver tissue. These data demonstrate complex differences in nicotine sensitivity and metabolism driven by genetic differences between C57BL/6J and NOD/ShiLtJ inbred mouse strains.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.

Brain Magnetic Resonance Imaging Features of Nicotine-Dependent Individuals and Its Correlation with Polymorphisms of Dopamine D Receptor Gene.

The aim of this research was developed to provide a scientific basis for individualized prevention, clinical diagnosis, and corrective treatment of nicotine addiction. The objects were 214 cases in the smoke group and 43 cases in the control group. According to the Fagerstrom Nicotine Dependence Test (FTND), the smokers were divided into mild nicotine dependence group (FTND < 6 points, 138 cases) and nicotine severe dependence group (≥6 points, 76 cases). The brain structure in long-term smokers was evaluated by using magnetic resonance imaging (MRI). The nicotine dependence was further analyzed by grouping the included individuals, and some candidate genes related to nicotine addiction were screened by combining with bioinformatics analysis. The family research strategy was adopted to detect nicotine addiction susceptibility genes and their polymorphisms. The MRI imaging results showed that the bilateral thalamus, right parietal, and left lens gram-molecule volume (GMV) were negatively correlated with smoking index and smoking years in the smoking group. The GMV of the posterior cingulate cortex in the severe nicotine dependence group was lower than that of the control group, and the GMVs of bilateral thalamus and bilateral superior limbic gyrus in the mild nicotine dependence group were lower than those of the control group. The gene polymorphism detection showed that rs6275 was highly polymorphic in the target population and the frequency of rs6275-C allele was 53.26%. Therefore, the MRI imaging characteristics suggested that the affected brain regions of smokers and people with varying degrees of nicotine dependence were mainly concentrated in response-related pathways and the limbic system and had cumulative effects on the central nervous system. In addition, the M6275 polymorphism of DRD2 gene was associated with susceptibility to nicotine addiction in Chinese population, and the M6275-C allele had a protective effect on susceptibility to nicotine addiction and smoking initiation.