Background

Cannabis users are highly likely to also be tobacco cigarette smokers and a proportion of this comorbidity is attributable to shared genetic influences. Three large meta-analyses of genomewide association studies (GWAS) of tobacco smoking have identified multiple genomewide significant (p<5×10(-8)) single nucleotide polymorphisms (SNPs). We examine whether these SNPs are associated with tobacco smoking and with cannabis involvement in an independent sample.

Method

Eleven SNPs associated with cigarettes per day (CPD), ever versus never smoking and current smoking/smoking cessation at p<5×10(-8) were selected from three published meta-analyses. Association analyses were conducted with similar tobacco smoking measures in 2716 European-American subjects from the Study of Addictions Genes and Environment (SAGE) and with lifetime and current cannabis use and DSM-IV cannabis abuse/dependence.

Results

Cannabis use and tobacco smoking correlated at 0.54. Rs16969968 in CHRNA5 (and its proxy, rs1051730 in CHRNA3) and rs1451240, a proxy for rs13280604 in CHRNB3, were associated with CPD after Bonferroni correction (p<0.006). rs1451240 was also associated with DSM-IV cannabis abuse/dependence. Rs6265 in BDNF was associated with smoking initiation, as in the original meta-analysis and also with lifetime cannabis use. Associations with cannabis involvement were no longer significant upon adjustment for the tobacco smoking measures.

Conclusions

The modest associations between cannabis involvement and SNPs for tobacco smoking were not independent of the comorbidity between tobacco and cannabis involvement. Larger samples of individuals might be required to articulate the specific genetic architecture of cannabis involvement.

Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9-12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23-2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27-2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36-0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45-2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.

Importance

Although early mortality in severe psychiatric illness is linked to smoking and alcohol, to our knowledge, no studies have comprehensively characterized substance use behavior in severe psychotic illness. In particular, recent assessments of substance use in individuals with mental illness are based on population surveys that do not include individuals with severe psychotic illness.

Objective

To compare substance use in individuals with severe psychotic illness with substance use in the general population.

Design, setting, and participants

We assessed comorbidity between substance use and severe psychotic disorders in the Genomic Psychiatry Cohort. The Genomic Psychiatry Cohort is a clinically assessed, multiethnic sample consisting of 9142 individuals with the diagnosis of schizophrenia, bipolar disorder with psychotic features, or schizoaffective disorder, and 10,195 population control individuals.

Main outcomes and measures

Smoking (smoked >100 cigarettes in a lifetime), heavy alcohol use (>4 drinks/day), heavy marijuana use (>21 times of marijuana use/year), and recreational drug use.

Results

Relative to the general population, individuals with severe psychotic disorders have increased risks for smoking (odds ratio, 4.6; 95% CI, 4.3-4.9), heavy alcohol use (odds ratio, 4.0; 95% CI, 3.6-4.4), heavy marijuana use (odds ratio, 3.5; 95% CI, 3.2-3.7), and recreational drug use (odds ratio, 4.6; 95% CI, 4.3-5.0). All races/ethnicities (African American, Asian, European American, and Hispanic) and both sexes have greatly elevated risks for smoking and alcohol, marijuana, and drug use. Of specific concern, recent public health efforts that have successfully decreased smoking among individuals younger than age 30 years appear to have been ineffective among individuals with severe psychotic illness (interaction effect between age and severe mental illness on smoking initiation, P = 4.5 × 105).

Conclusions and relevance

In the largest assessment of substance use among individuals with severe psychotic illness to date, we found the odds of smoking and alcohol and other substance use to be dramatically higher than recent estimates of substance use in mild mental illness.

Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this study, we developed a novel approach to "infer" the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure to assess its operating characteristics. We applied the dTDT to the simulated data and documented the power of the dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals. One SNP (rs4903712 on chromosome 14) remained significant after correcting for multiple testing Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data.

Objective

Variations in the genes encoding alcohol dehydrogenase (ADH) enzymes are associated with both alcohol consumption and dependence in multiple populations. Additionally, some environmental factors have been recognized as modifiers of these relationships. This study examined the modifying effect of religious involvement on relationships between ADH gene variants and alcohol consumption-related phenotypes.

Method

Subjects were African American, European American, and Hispanic American adults with lifetime exposure to alcohol (N = 7,716; 53% female) from the Collaborative Study on the Genetics of Alcoholism. Genetic markers included ADH1Brs1229984, ADH1B-rs2066702, ADH1C-rs698, ADH4-rs1042364, and ADH4-rs1800759. Phenotypes were maximum drinks consumed in a 24-hour period and total number of alcohol dependence symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Religious involvement was defined by self-reported religious services attendance.

Results

Both religious involvement and ADH1B-rs1229984 were negatively associated with the number of maximum drinks consumed and the number of lifetime alcohol dependence symptoms endorsed. The interactions of religious involvement with ADH1B-rs2066702, ADH1C-rs698, and ADH4-rs1042364 were significantly associated with maximum drinks and alcohol dependence symptoms. Risk variants had weaker associations with maximum drinks and alcohol dependence symptoms as a function of increasing religious involvement.

Conclusions

This study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms.

Aims

Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence.

Design

We examined consistency of association across studies and race between the α6β3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies.

Setting

United States of America.

Participants

European Americans and African Americans from three case-control studies of substance dependence.

Measurements

Subjects were evaluated using the Semi-Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerström Test for Nicotine Dependence.

Findings

The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups [odds ratio (OR) = 0.75, P = 5.8 × 10(-4) European Americans; OR = 0.80, P = 0.05 African Americans]. No other substance dependence was associated consistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442.

Conclusions

The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.

The collaborative study on the genetics of alcoholism (COGA) is a multi-site, multidisciplinary project with the goal of identifying how genes are involved in alcohol use disorder and related outcomes, and characterizing how genetic risk unfolds across development and in conjunction with the environment and brain function. COGA is a multi-generational family-based study in which probands were recruited through alcohol treatment centers, along with a set of community comparison families. Nearly 18,000 individuals from >2200 families have been assessed over a period of over 30 years with a rich phenotypic battery that includes semi-structured psychiatric interviews and questionnaire measures, along with DNA collection and electrophysiological data on a large subset. Participants range in age from 7 to 97, with many having longitudinal assessments, providing a valuable opportunity to study alcohol use and problems across the lifespan. Here we provide an overview of data collection methods for the COGA sample, and details about sample characteristics and comorbidity. We also review key research findings that have emerged from analyses of the COGA data. COGA data are available broadly to researchers, and we hope this overview will encourage further collaboration and use of these data to advance the field.

Background

All stages of development of alcohol use disorder (AUD) have not been equally studied. While initiation of drinking has been given considerable attention, other stages have not been as thoroughly investigated. It is not clear whether the same factors are associated consistently across early and late transitions in AUD involvement. High-risk family samples that are enriched for AUD vulnerability and transitions in AUD development offer an opportunity to examine influences across multiple stages of AUD development.

Methods

Data from adolescents and young adults from high-risk families were used to study 4 transitions in AUD development-time to first drink, first drink to first problem, first drink to first diagnosis, and first problem to first diagnosis. Cox modeling was used to compare associations of parental AUD, parental separation, peer substance use, offspring ever-use of cannabis, trauma exposures, and internalizing and externalizing psychopathology across transitions.

Results

Hazards of most transitions were elevated for those who had ever used cannabis, those who attributed substance use to their peers, those with externalizing disorders, and those with parents with AUD. Many risk factors were linked to early initiation of alcohol, particularly cannabis use. Internalizing disorders were associated with later stages. Nonassaultive trauma was associated only with early initiation; assaultive trauma was not associated with any transition.

Conclusions

In this large, ethnically diverse sample of high-risk youth, significant influences across transitions were fairly consistent, with externalizing disorders and cannabis ever-use elevating the likelihood of each stage, and peer and parental (and especially maternal AUD) influences linked to initiation and some later stages. Finally, in light of the increasingly permissive legal and social stances toward cannabis in the United States, the marked elevations of all alcohol outcomes observed for cannabis use underscore the importance of studying the underpinnings of this relationship.

Alcohol and drug use disorders are individually heritable (50%). Twin studies indicate that alcohol and substance use disorders share common genetic influences, and therefore may represent a more heritable form of addiction and thus be more powerful for genetic studies. This study utilized data from 2322 subjects from 118 European-American families in the Collaborative Study on the Genetics of Alcoholism sample to conduct genome-wide association analysis of a binary and a continuous index of general substance dependence liability. The binary phenotype (ANYDEP) was based on meeting lifetime criteria for any DSM-IV dependence on alcohol, cannabis, cocaine or opioids. The quantitative trait (QUANTDEP) was constructed from factor analysis based on endorsement across the seven DSM-IV criteria for each of the four substances. Heritability was estimated to be 54% for ANYDEP and 86% for QUANTDEP. One single-nucleotide polymorphism (SNP), rs2952621 in the uncharacterized gene LOC151121 on chromosome 2, was associated with ANYDEP (P = 1.8 × 10(-8) ), with support from surrounding imputed SNPs and replication in an independent sample [Study of Addiction: Genetics and Environment (SAGE); P = 0.02]. One SNP, rs2567261 in ARHGAP28 (Rho GTPase-activating protein 28), was associated with QUANTDEP (P = 3.8 × 10(-8) ), and supported by imputed SNPs in the region, but did not replicate in an independent sample (SAGE; P = 0.29). The results of this study provide evidence that there are common variants that contribute to the risk for a general liability to substance dependence.

Background

Adolescent drinking is an important public health concern, one that is influenced by both genetic and environmental factors. The functional variant rs1229984 in alcohol dehydrogenase 1B (ADH1B) has been associated at a genome-wide level with alcohol use disorders in diverse adult populations. However, few data are available regarding whether this variant influences early drinking behaviors and whether social context moderates this effect. This study examines the interplay between rs1229984 and peer drinking in the development of adolescent drinking milestones.

Methods

One thousand five hundred and fifty European and African American individuals who had a full drink of alcohol before age 18 were selected from a longitudinal study of youth as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Cox proportional hazards regression, with G × E product terms in the final models, was used to study 2 primary outcomes during adolescence: age of first intoxication and age of first DSM-5 alcohol use disorder symptom.

Results

The minor A allele of rs1229984 was associated with a protective effect for first intoxication (HR = 0.56, 95% CI 0.41 to 0.76) and first DSM-5 symptom (HR = 0.45, 95% CI 0.26 to 0.77) in the final models. Reporting that most or all best friends drink was associated with a hazardous effect for first intoxication (HR = 1.81, 95% CI 1.62 to 2.01) and first DSM-5 symptom (HR = 2.17, 95% 1.88 to 2.50) in the final models. Furthermore, there was a significant G × E interaction for first intoxication (p = 0.002) and first DSM-5 symptom (p = 0.01). Among individuals reporting none or few best friends drinking, the ADH1B variant had a protective effect for adolescent drinking milestones, but for those reporting most or all best friends drinking, this effect was greatly reduced.

Conclusions

Our results suggest that the risk factor of best friends drinking attenuates the protective effect of a well-established ADH1B variant for 2 adolescent drinking behaviors. These findings illustrate the interplay between genetic and environmental factors in the development of drinking milestones during adolescence.