Illicit drug use and abuse/dependence: modeling of two-stage variables using the CCC approach

doi:10.1016/j.addbeh.2004.09.007

Addictive Behaviors

Volume 30, Issue 5, June 2005, Pages 1043-1048

https://doi.org/10.1016/j.addbeh.2004.09.007 Get rights and content

Abstract

Drug use and abuse/dependence are stages of a complex drug habit. Most genetically informative models that are fit to twin data examine drug use and abuse/dependence independent of each other. This poses an interesting question: for a multistage process, how can we partition the factors influencing each stage specifically from the factors that are common to both stages? We used a causal-common-contingent (CCC) model to partition the common and specific influences on drug use and abuse/dependence. Data on use and abuse/dependence of cannabis, cocaine, sedatives, stimulants and any illicit drug was obtained from male and female twin pairs. CCC models were tested individually for each sex and in a sex-equal model. Our results suggest that there is evidence for additive genetic, shared environmental and unique environmental influences that are common to illicit drug use and abuse/dependence. Furthermore, we found substantial evidence for factors that were specific to abuse/dependence. Finally, sexes could be equated for all illicit drugs. The findings of this study emphasize the need for models that can partition the sources of individual differences into common and stage-specific influences.

Introduction

Illicit drug use is moderately heritable (26–40% due to genetic factors or A) with evidence for the role of shared environmental (environment shared by members of a twin pair or C) and individual-specific environmental factors (E). Abuse/dependence of illicit drugs is highly heritable (28–79% due to A) with the remainder of the variance due to individual-specific environmental influences (Kendler et al., 2000, Kendler et al., 1999a, Tsuang et al., 2001, Van den Bree et al., 1998). However, drug involvement is a two-stage process where drug use (the so-called “upstream” variable), in certain cases, is followed by the clinically diagnosed stage of abuse/dependence (the “downstream” variable). This contingent nature (use must precede abuse/dependence) was not considered in previous univariate models. The causal-common-contingent (CCC) model is an improvement over the standard independent assessments of drug use and abuse/dependence (Kendler, Neale, & Sullivan et al., 1999). The model allows for partitioning of genetic and environmental factors common to drug use and abuse/dependence from the factors that are unique to abuse/dependence. Using the CCC model, in the present study we sought to examine the role of common and specific additive genetic (A), shared environmental (C) and unique environmental (E) factors on the two stages (use and abuse/dependence) of cannabis, cocaine, sedatives, stimulants and any illicit drug involvement and test for the presence of quantitative gender differences.

Section snippets

Sample

This study utilized drug use and abuse/dependence information from 1191 (702 MZ and 489 DZ pairs) male and 934 (556 MZ and 378 DZ pairs) female same-sex monozygotic (MZ) and dizygotic (DZ) Caucasian twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD), a longitudinal study based on participants from the Virginia Twin Registry (now a part of the Mid-Atlantic Twin Registry). The most recent and complete waves of interview were used for these

Results

Mean age of the female twins was 35.8 years (range 21–62 years) at the fourth wave of interviews with a mean education level of 14.3 years. The male twin pairs had a mean age of 35.5 years (range 20–58 years) and a mean education level of 13.6 years at the second wave of interviews. Standardized parameter estimates for each illicit drug are presented in Table 1, separately for males and females. For all the illicit drugs, except sedatives, a_i² ranges between 0.48 and 0.73, c_i² ranges between

Discussion

Drug use and abuse/dependence should be modeled as a two-stage process. Previous studies have typically modeled use and abuse/dependence, individually, without considering the contingent relationship between them. Two previous studies used data from the same data set to assess use and abuse/dependence with the CCC approach. In this study, we sought to obtain the best estimates of additive genetic, shared environmental and unique environmental factors on illicit drug use and abuse/dependence

Acknowledgements

This work was supported by NIH grants MH-40828, MH/AA/DA-49492, AA-09095 and DA-11287. We acknowledge the contribution of the Virginia Twin Registry, now part of the Mid-Atlantic Twin Registry (MATR), for ascertainment of subjects for this study. The MATR, directed by Dr. J Silberg, L Corey and L. Eaves, has received support from the National Institutes of Health, the Carman Trust and the WM Keck, John Templeton and Robert Wood Johnson Foundations.

References (12)

J.A. Kauer
Addictive drugs and stress trigger a common change at VTA synapses
Neuron
(2003)
M.B. van den Bree et al.
Genetic and environmental influences on drug use and abuse/dependence in male and female twins
Drug and Alcohol Dependence
(1998)
H. Akaike
Factor analysis and AIC
Psychometrika
(1987)
American Psychiatric Association
Diagnostic and statistical manual of mental disorders
(1994)
K.S. Kendler et al.
Genetic and environmental risk factors in the aetiology of illicit drug initiation and subsequent misuse in women
British Journal of Psychiatry
(1999)
K.S. Kendler et al.
Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins
Archives of General Psychiatry
(2000)

There are more references available in the full text version of this article.

Cited by (58)

Cannabis use in college: Genetic predispositions, peers, and activity participation
2021, Drug and Alcohol Dependence
Citation Excerpt :
These genetic correlations suggest that some of the genetic liability indexed by our PRS is not specific to cannabis use and may reflect a more general liability for psychopathology. Additionally, the genetic etiology of substance use initiation and substance use escalation vary (Agrawal et al., 2005), suggesting that additional information may be gained by examining PRS for cannabis consumption and cannabis use disorder. In summary, social contexts and their interactions with genetic risks were important predictors of recent cannabis use.
Among adult college students in the US, cannabis use is common and associated with considerable negative consequences to health, cognition, and academic functioning, underscoring the importance of identifying risk and protective factors. Cannabis use is influenced by genetic factors, but genetic risk is not determinative. Accordingly, it is critical to identify environments that reduce risk among those who are at elevated genetic risk. This study examined the impact of polygenic scores for cannabis initiation, various forms of social activity participation, and peer deviance on recent cannabis use. Our aim was to test whether these environments moderate genetic risk for cannabis use.
Data came from a longitudinal sample of undergraduate college students of European American (EA; N_EA = 750) and African American (AA; N_AA = 405) ancestry. Generalized estimating equations with a logit link function were used to examine main effects and two-way interactions.
Engagement with church activities was associated with lower probability of cannabis use. Peer deviance was associated with higher probability of cannabis use. Engagement with community activities moderated the influence of the polygenic risk score in the EA sample, such that PRS was associated with recent cannabis use among those who never engaged in community activities. This effect did not replicate in AAs, which may have been due to the portability of PRS based on EA discovery samples.
Results suggest that community activities may limit the influence of genetic risk, as associations between PRS and cannabis use were only observed among individuals who never engaged in community activities.
Neuroepigenetics and addiction
2018, Handbook of Clinical Neurology
Drug addiction involves long-term behavioral abnormalities that arise in response to repeated exposure to drugs of abuse in vulnerable individuals. It is a multifactorial syndrome involving a complex interplay between genes and the environment. Evidence suggests that the underlying mechanisms regulating these persistent behavioral abnormalities involve changes in gene expression throughout the brain's reward circuitry, in particular, in the mesolimbic dopamine system. In the past decade, investigations have begun to reveal potential genes involved in the risk for addiction through genomewide association studies. Additionally, a crucial role for epigenetic mechanisms, which mediate the enduring effects of drugs of abuse on the brain in animal models of addiction, has been established. This chapter focuses on recent evidence that genetic and epigenetic regulatory events underlie the changes throughout the reward circuitry in humans, as well as animal models of addiction. While further investigations are necessary, a picture of genetic and epigenetic mechanisms involved in addiction is beginning to emerge and the insight gained from these studies will be key to the identification of novel targets for improved diagnosis and treatment of addiction syndromes in humans.
Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans
2016, Drug and Alcohol Dependence
Citation Excerpt :
Due to the modest sample size, which could lead to false negatives, subjects who had never used cannabis were included. There are two reasons why this likely does not mitigate the results of this study: (1) a recent meta-analysis suggested that environmental influences play a larger role in cannabis initiation than CUD (Verweij et al., 2010), and (2) there may be some overlap in genetic influences between cannabis initiation and CUD (Agrawal et al., 2005; Fowler et al., 2007; Gillespie et al., 2009). Finally, as with other human genetic studies, replication is needed to support our findings.
Cannabis is a commonly used drug and studies have shown that a significant portion of the variation in cannabis use disorders (CUDs) is heritable. Five genes known to play a role in the endocannabinoid system and CUDs were examined in a community sample of young adult Mexican Americans (MAs): CNR1, MGLL, FAAH, DAGLA, and DAGLB.
Gene-based tests were run to test for association between each gene and two DSM-5 cannabis phenotypes. Subsequent linear regressions were run in PLINK using an additive model to determine which single nucleotide polymorphisms (SNPs) were driving the association.
FAAH was significantly associated with DSM-5 cannabis use disorder group count (DSM-5 CUD) using a gene-based test (p = 0.0035). This association survived Bonferroni correction for multiple testing at p < 0.004. Post hoc analyses suggested this association was driven by two common (minor allele frequency >5%) SNPs in moderate linkage disequilibrium, rs324420 and rs4141964, at p = 0.0014 and p = 0.0023, respectively. In both cases the minor allele increased risk for DSM-5 CUD.
Genetic variation in FAAH was associated with DSM-5 CUD in MAs. This association was primarily driven by the missense SNP rs324420. In vitro work has provided evidence that the risk allele generates an enzyme with decreased expression and cellular stability. Although this SNP has been previously associated with substance use in the literature, this is the first association in a young adult MA sample.
Two-part random effects growth modeling to identify risks associated with alcohol and cannabis initiation, initial average use and changes in drug consumption in a sample of adult, male twins
2012, Drug and Alcohol Dependence
Citation Excerpt :
With respect to etiology, it is possible that drug-specific covariates risks account for some of the unshared variance between alcohol and cannabis use, or for aspects of the genetic and environmental influences known to be uncorrelated across drug use phenotypes (Kendler et al., 2007b, 2003b). Likewise, any risks that predict initiation but not average use may account for the proportion of genetic and environmental liability in drug initiation that does not overlap with measures of chronic use and abuse (Agrawal and Lynskey, 2006; Agrawal et al., 2005; Gillespie et al., 2009b). An assumption implicit in many previous reports (Boyle et al., 1992; Dishion and Loeber, 1985a; Fergusson and Lynskey, 1998; Freisthler et al., 2005; Helzer et al., 1992; Kandel et al., 1978; Kendler et al., 1997; Lynskey and Hall, 2001; McDermott, 1984; McGue et al., 1999; Szobot and Bukstein, 2008; Werner, 1982; Werner and Smith, 1989; Young et al., 1995) is that the etiology of risks is entirely environmental and antecedent to drug use.
Our aim was to profile alcohol and cannabis initiation and to characterize the effects of developmental and environmental risk factors on changes in average drug use over time.
We fitted a two-part random effects growth model to identify developmental and environmental risks associated with alcohol and cannabis initiation, initial average use and changes in average use.
1796 males aged 24–63 from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.
Data from three interview waves included self-report measures of average alcohol and cannabis use between ages 15 and 24, genetic risk of problem drug use, childhood environmental risks, personality, psychiatric symptoms, as well as personal, family and social risk factors.
Average alcohol and cannabis use were correlated at all ages. Genetic risk of drug use based on family history, higher sensation seeking, and peer group deviance predicted both alcohol and cannabis initiation. Higher drug availability predicted cannabis initiation while less parental monitoring and drug availability were the best predictors of how much cannabis individuals consumed over time.
The liability to initiate alcohol and cannabis, average drug use as well as changes in drug use during teenage years and young adulthood is associated with known risk factors.
Are prescription misuse and illicit drug use etiologically distinct? A genetically-informed analysis of opioids and stimulants
2022, Psychological Medicine
Genetics of substance use disorders: A review
2021, Psychological Medicine

View all citing articles on Scopus

View full text

Short communicationIllicit drug use and abuse/dependence: modeling of two-stage variables using the CCC approach

Abstract

Introduction

Section snippets

Sample

Results

Discussion

Acknowledgements

Neuron

Drug and Alcohol Dependence

Factor analysis and AIC

Psychometrika

Diagnostic and statistical manual of mental disorders

Genetic and environmental risk factors in the aetiology of illicit drug initiation and subsequent misuse in women

British Journal of Psychiatry

Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins

Archives of General Psychiatry

Short communication
Illicit drug use and abuse/dependence: modeling of two-stage variables using the CCC approach