Patterns and Correlates of Polysubstance Use Among Individuals With Severe Alcohol Use Disorder.

AIM: The present study examined patterns and correlates of polysubstance use among individuals with severe alcohol use disorder (AUD). METHODS: Participants were 2785 individuals (63% female; mean age = 43 years, range = 18-78 years) from the Genes, Addiction and Personality Study. All participants met lifetime criteria for severe AUD (6+ symptoms). We used latent class analysis to identify patterns of frequency of lifetime use for cigarettes, marijuana, cocaine, stimulants, sedatives, opioids and hallucinogens. A variety of demographic and behavioral correlates of latent class membership were tested in univariable and multivariable models. RESULTS: A five-class solution was selected: extended range polysubstance use (24.5%); cigarette and marijuana use (18.8%); 'testers,' characterized by high probabilities of smoking 100 or more cigarettes, using marijuana 6+ times, and trying the remaining substances 1-5 times (12.3%); moderate range polysubstance use (17.1%) and minimal use (reference class; 27.3%). In univariable analyses, all potential correlates were related to latent class membership. In the multivariable model, associations with gender, race/ethnicity, age of onset for alcohol problems, dimensions of impulsivity, depressive symptoms, antisocial behavior and family history density of alcohol problems remained significant, though the pattern and strength of associations differed across classes. For instance, sensation-seeking, lack of premeditation and family history were uniquely associated with membership in the extended range polysubstance use class. CONCLUSION: Patterns of polysubstance use are differentially related to demographic and behavioral factors among individuals with severe AUD. Assessing use across multiple substances may inform the selection of targets for treatment and prevention.

Intermediate stable states in substance use.

Many people across the world use potentially addictive legal and illegal substances, but evidence suggests that not all use leads to heavy use and dependence, as some substances are used moderately for long periods of time. Here, we empirically examine, the stability of and transitions between three substance use states: zero-use, moderate use, and heavy use. We investigate two large datasets from the US and the Netherlands on yearly usage and change of alcohol, nicotine, and cannabis. Results, which we make available through an extensive interactive tool, suggests that there are stable moderate use states, even after meeting criteria for a positive diagnosis of substance abuse or dependency, for both alcohol and cannabis use. Moderate use of tobacco, however, was rare. We discuss implications of recognizing three states rather than two states as a modeling target, in which the moderate use state can both act as an intervention target or as a gateway between zero use and heavy use.

Specific antisocial and borderline personality disorder criteria and general substance use: A twin study.

Antisocial (ASPD) and borderline (BPD) personality disorders (PDs) are associated with increased risk for substance use. They are "specific" risk factors among PDs in that they withstand adjusting for the other PDs, whereas the reverse does not hold. Specificity is a classic sign of causation. This empirical work addresses 3 further problems that can undermine causal inferences in personality and substance-use research: hierarchical nature of etiologic factors in psychiatry, imperfectly operationalized PD criteria, and possible genetic or environmental confounding, as seen in lack of "etiologic continuity." We used exploratory structural equation bifactor modeling and biometric models to mitigate these problems. The participants were Norwegian adult twins of ages 19-36 years (N = 2,801). Criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), PDs were assessed using a structured interview. General substance-use risk was indicated by World Health Organization Composite International Diagnostic Interviewed alcohol use disorder and illicit drug use, and by self-reported regular smoking. A general risk factor for all criteria of both ASPD and BPD was the strongest individual correlate of general substance use and showed etiologic continuity, though just 3 specific PD criteria could predict substance use to the same extent. The findings indicate that a broad latent factor for both ASPD and BPD may be a specific and a genetically and environmentally unconfounded risk factor for substance use. Substance-use treatment research might benefit from attending to transdiagnostic models of ASPD, BPD, and related behavioral disinhibition. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A Twin Study of Cigarette and Snus Initiation and Quantity of Use in Norwegian Adult Twins.

While snus has been the focus of increasing public health interest, twin studies have examined neither sources of individual variation for its use nor the sources of resemblance between snus and cigarette use. Twins from the Norwegian Institute of Public Health Panel were assessed by self-report questionnaire for the initiation of regular use and maximal quantity used for snus and cigarettes. Twin modeling was performed using OpenMx on data from 2767 twins including 856 complete pairs. Fitting univariate twin models produced similar results for cigarette initiation and quantity with estimates of additive genetic, shared environmental and unique environmental effects of approximately 77%, 0% and 23%, respectively. Estimates of snus initiation and quantity were, respectively, approximately 53%, 26% and 21%. Joint analyses suggested that the genetic, shared environmental and unique environmental correlations between cigarette and snus initiation and quantity were +.82, 0 and +.42, respectively. However, these results could not be statistically distinguished from a model which postulated that resemblance between cigarette initiation and quantity resulted from genetic and unique environmental correlations of +.47 and +.43. Compared with cigarette initiation and quantity of use in Norwegian twins, the role of genes was less prominent and shared environment more prominent for initiation and quantity of use of snus. Joint analyses of both tobacco phenotypes suggested, but did not confirm definitively, that genetic risk factors for cigarette and snus use were similar but not identical, while shared environmental factors existed that were specific to snus use.

Genetic risks to nicotine dependence predict negative mood and affect in current non-smokers.

Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug, and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively), and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence.

Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.

CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure.

Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p = 0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions.

Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample.

BACKGROUND: While genetic influences on alcohol dependence (AD) are substantial, progress in the identification of individual genetic variants that impact on risk has been difficult. METHODS: We performed a genome-wide association study on 3,169 alcohol consuming subjects from the population-based Molecular Genetics of Schizophrenia (MGS2) control sample. Subjects were asked 7 questions about symptoms of AD which were analyzed by confirmatory factor analysis. Genotyping was performed using the Affymetrix 6.0 array. Three sets of analyses were conducted separately for European American (EA, n = 2,357) and African-American (AA, n = 812) subjects: individual single nucleotide polymorphisms (SNPs), candidate genes and enriched pathways using gene ontology (GO) categories. RESULTS: The symptoms of AD formed a highly coherent single factor. No SNP approached genome-wide significance. In the EA sample, the most significant intragenic SNP was in KCNMA1, the human homolog of the slo-1 gene in C. Elegans. Genes with clusters of significant SNPs included AKAP9, phosphatidylinositol glycan anchor biosynthesis, class G (PIGG), and KCNMA1. In the AA sample, the most significant intragenic SNP was CEACAM6 and genes showing empirically significant SNPs included KCNQ5, SLC35B4, and MGLL. In the candidate gene based analyses, the most significant findings were with ADH1C, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and ankyrin repeat and kinase domain containing 1 (ANKK1) in the EA sample, and ADH5, POMC, and CHRM2 in the AA sample. The ALIGATOR program identified a significant excess of associated SNPs within and near genes in a substantial number of GO categories over a range of statistical stringencies in both the EA and AA sample. CONCLUSIONS: While we cannot be highly confident about any single result from these analyses, a number of findings were suggestive and worthy of follow-up. Although quite large samples will be needed to obtain requisite power, the study of AD symptoms in general population samples is a viable complement to case-control studies in identifying genetic risk variants for AD.

Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence.

Nicotinic acetylcholine receptors bind to nicotine and initiate the physiological and pharmacological responses to tobacco smoking. In this report, we studied the association of alpha5 and alpha3 subunits with nicotine dependence and with the symptoms of alcohol and cannabis abuse and dependence in two independent epidemiological samples (n = 815 and 1,121, respectively). In this study, seven single nucleotide polymorphisms were genotyped in the CHRNA5 and CHRNA3 genes. In both samples, we found that the same alleles of rs16969968 (P = 0.0068 and 0.0028) and rs1051730 (P = 0.0237 and 0.0039) were significantly associated with the scores of Fagerström test for nicotine dependence (FTND). In the analyses of the symptoms of abuse/dependence of alcohol and cannabis, we found that rs16969968 and rs1051730 were significantly associated with the symptoms of alcohol abuse or dependence (P = 0.0072 and 0.0057) in the combined sample, but the associated alleles were the opposite of that of FTND. No association with cannabis abuse/dependence was found. These results suggested that the alpha5 and alpha3 subunits play a significant role in both nicotine dependence and alcohol abuse/dependence. However, the opposite effects with nicotine dependence and alcohol abuse/dependence were puzzling and future studies are necessary to resolve this issue.

Cannabinoid receptor 1 gene association with nicotine dependence.

CONTEXT: The endogenous cannabinoid system has been implicated in drug addiction in animal models. The cannabinoid receptor 1 (CNR1) gene is 1 of the 2 receptors expressed in the brain. It has been reported to be associated with alcoholism and multiple drug abuse and dependence. OBJECTIVE: To test the hypothesis that the CNR1 gene is associated with nicotine dependence. DESIGN: Genotype-phenotype association study. Ten single-nucleotide polymorphisms were genotyped in the CNR1 gene in 2 independent samples. For the first sample (n = 688), a 3-group case-control design was used to test allele association with smoking initiation and nicotine dependence. For the second sample (n = 961), association was assessed with scores from the Fagerström Test for Nicotine Dependence (FTND). Settings Population samples selected from the Mid-Atlantic Twin Registry. PARTICIPANTS: White patients aged 18 to 65 years who met the criteria of inclusion. MAIN OUTCOME MEASURES: Fagerström Tolerance Questionnaire and FTND scores. RESULTS: Significant single-marker and haplotype associations were found in both samples, and the associations were female specific. Haplotype 1-1-2 of markers rs2023239-rs12720071-rs806368 was associated with nicotine dependence and FTND score in the 2 samples (P < .001 and P = .009, respectively). CONCLUSION: Variants and haplotypes in the CNR1 gene may alter the risk for nicotine dependence, and the associations are likely sex specific.

Genetic and environmental influences on alcohol, caffeine, cannabis, and nicotine use from early adolescence to middle adulthood.

CONTEXT: While both environmental and genetic factors are important in the etiology of psychoactive substance use (PSU), we know little of how these influences differ through development. OBJECTIVE: To clarify the changing role of genes and environment in PSU from early adolescence through middle adulthood. DESIGN: Retrospective assessment by life history calendar, with univariate and bivariate structural modeling. SETTING: General community. PARTICIPANTS: A total of 1796 members of male-male pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. MAIN OUTCOME MEASURES: Levels of use of alcohol, caffeine, cannabis, and nicotine recorded for every year of the respondent's life. RESULTS: For nicotine, alcohol, and cannabis, familial environmental factors were critical in influencing use in early adolescence and gradually declined in importance through young adulthood. Genetic factors, by contrast, had little or no influence on PSU in early adolescence and gradually increased in their effect with increasing age. The sources of individual differences in caffeine use changed much more modestly over time. Substantial correlations were seen among levels of cannabis, nicotine, and alcohol use and specifically between caffeine and nicotine. In adolescence, those correlations were strongly influenced by shared effects from the familial environment. However, as individuals aged, more and more of the correlation in PSU resulted from genetic factors that influenced use of both substances. CONCLUSIONS: These results support an etiologic model for individual differences in PSU in which initiation and early patterns of use are strongly influenced by social and familial environmental factors while later levels of use are strongly influenced by genetic factors. The substantial correlations seen in levels of PSU across substances are largely the result of social environmental factors in adolescence, with genetic factors becoming progressively more important through early and middle adulthood.

Characteristics of monozygotic male and female twins discordant for overweight: a descriptive study.

OBJECTIVES: BMI is highly heritable. Yet, trends in obesity highlight environmental influences on body weight. Monozygotic (MZ) twins discordant for overweight offer a unique opportunity to examine these factors. METHODS: MZ male (n=8 pairs) and female twins (n=10 pairs) discordant for overweight (defined as the BMI of one twin being at least 24.5, and the BMI of his/her co-twin being below 24.5 and at least three points lower) were identified from the Mid-Atlantic Twin Registry. Variables were assessed via self-report questionnaires. RESULTS: One overweight and two non-overweight females met criteria for bulimia nervosa. Rates of dieting and binge eating were high among all males and females. Hunger scores were higher among non-overweight females; disinhibition scores were higher among overweight males. Only one non-overweight and three overweight males smoked; 90% of non-overweight and 40% of overweight females smoked. CONCLUSIONS: Assessing tobacco use and eating disorders may be important when sampling on the basis of family members who are discordant for BMI. Finally, results suggest possibilities for interventions in individuals at-risk for overweight.

Longitudinal modeling of genetic and environmental influences on self-reported availability of psychoactive substances: alcohol, cigarettes, marijuana, cocaine and stimulants.

BACKGROUND: Although an obvious environmental factor influencing drug use, the sources of individual differences in drug availability (DA) are unknown. METHOD: This report is based on 1788 adult males from the Mid-Atlantic Twin Registry who participated in a structured telephone interview that included retrospective assessments of DA (cigarette, alcohol, marijuana, cocaine and stimulants) between ages 8 and 25. We fitted a biometric dual change score (DCS) model, adapted for ordinal data, to model latent growth and estimate the genetic and environmental components of variance over time. RESULTS: DA, despite being considered an environmental risk factor, is under both genetic and environmental control. For cigarette, alcohol, marijuana and cocaine availability, there was an overall increase in additive genetic variance and a decline in shared environmental variance over time. Non-shared environmental variance remained steady. Stimulant availability did not follow this pattern. Instead, there was an upswing in shared environmental effects with increasing age. CONCLUSION: We have modeled the genetic and environmental architecture of changes in DA across adolescence. The rise in additive genetic variance over time coincides with acceleration in the expression of individual differences, probably brought on by an increase in personal freedom and a reduction in social constraints. Understanding the etiology of DA is likely to reveal key components, acting directly or indirectly, in the pathway(s) leading to drug initiation, abuse and dependence.

Level of family dysfunction and genetic influences on smoking in women.

BACKGROUND: An adoption study of alcoholism suggests that in women, the impact of genetic risk factors become greater in the presence of conflict in the family of origin. Is the same true for cigarette smoking (CS)? METHOD: We obtained, in a sample of 1676 twins from female female twin pairs from a population-based register, a measure of maximum lifetime CS (divided into six ordinal categories) and family dysfunction (FD) assessed as the mean report of up to four informants (twin, co-twin, mother, father). Statistical analysis was conducted by traditional regression analysis and a moderator structural equation twin model using the computer program Mx. RESULTS: With increasing levels of FD, maximum CS increased substantially while correlations for CS in monozygotic (MZ) and dizygotic (DZ) twins decreased modestly. Regression analyses demonstrated reduced twin-pair resemblance for CS with increasing levels of FD. The best-fit structural equation model found high levels of heritability for CS and no evidence for a role of shared environment. With increasing levels of FD, the proportion of variance in CS due to genetic factors (i.e. heritability) decreased while that due to unique environmental effects increased. CONCLUSIONS: Several different statistical methods suggested that, contrary to prediction, heritability of CS decreased rather than increased with higher levels of dysfunction in the family of origin. The hypothesis that genetic effects for psychiatric and drug-use disorders become stronger in more adverse environments is not universally true.