Genetic etiology of the common liability to drug dependence: Evidence of common and specific mechanisms for DSM-IV dependence symptoms

Division of Behavioral Genetics, Rhode Island Hospital, United States. Rohan
Drug and alcohol dependence (Impact Factor: 3.42). 01/2012; 123 Suppl 1(Suppl 1):S24-32. DOI: 10.1016/j.drugalcdep.2011.12.015
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We investigated the etiological nature of comorbid alcohol, tobacco, and cannabis DSM-IV dependence symptoms in late adolescence and young adulthood while accounting for gender differences in the magnitude of genetic and environmental influences.
Univariate and multivariate twin modeling was used to determine the heritability of each substance and the etiology of multiple drug problems in a sample of 2484 registrants of the Center for Antisocial Drug Dependence who provided data at the second wave of an ongoing longitudinal study. We report on mean and prevalence levels of whole-life DSM-IV dependence symptoms that were assessed with the Composite International Diagnostic Interview-Substance Abuse Module. Biometrical analyses were limited to age-adjusted DSM-IV dependence symptom counts from a subset of twins that reported using alcohol, tobacco, or cannabis in their lifetime.
Male and female alcohol, tobacco, and cannabis DSM-IV symptoms are indicators of a heritable unidimensional latent continuous trait. Additive genetic factors explain more than 60% of the common liability to drug dependence. A larger proportion of the variation in each substance is attributable to substance-specific genetic and environmental factors.
These data suggest that both common and substance-specific genetic and environmental factors contribute to individual differences in the levels of DSM-IV alcohol, tobacco, and cannabis dependence symptoms.

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Available from: Michael C Stallings, Oct 13, 2015
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    • "As those studies estimate , this general addiction liability is significantly heritable . This trait, resulting from all non-substance-specific factors influencing addiction risk, is likely rooted in the basic mechanisms of behavior regulation, reward, affect, stress and socialization (Vanyukov et al. 2003b, 2012; Palmer et al. 2012). As many other complex (multifactorial ) traits, individual variation in which is determined by numerous organismic and environmental factors, addiction liability is likely a continuous trait and has a normal phenotypic distribution in the population, as per the central limit theorem. "
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    ABSTRACT: Transmissible liability index (TLI), developed employing a high-risk design and item response theory, enables quantification of the latent trait of liability to drug use disorders (DUD) in children. TLI has been shown to have high heritability and predict DUD in young adulthood. This study extends prior research and determines the genetic contribution of DUD liability measured by TLI to adult liability as indexed by DUD diagnosis. The study utilizes data from a twin sample tracked from age 11 to age 25. In addition to confirming TLI’s high heritability and predictive validity, it shows that the genetic component of variance in TLI assessed in childhood accounts for over half of the genetic variance in DUD diagnosis and the entire phenotypic relationship between the two liability measures. This validates TLI as an early measure of DUD liability and supports its utility in early-age genetic and other mechanistic studies of DUD.
    Behavior Genetics 12/2014; 45(1). DOI:10.1007/s10519-014-9684-4 · 3.21 Impact Factor
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    • "Similarly, religious service attendance decreased the risk for both disorders, pointing to shared pathways to the development and maintenance of these disorders, as previously suggested (Lopez-Quintero et al., 2011; Palmer et al., 2012). By contrast, predictors of lifetime smoking and lifetime cannabis use M a n u s c r i p t 19 have substantial differences, possibly suggesting substance-specific risk factors for drug use initiation but common liability for drug dependence (Palmer et al., 2012). "
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    ABSTRACT: Background This study aims to identify predictors of smoking initiation and nicotine dependence (ND) to develop a comprehensive risk-factor model based on Kendler's development model for major depression. Methods Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), Wave 2 (n = 34,653). Risk factors were divided into 5 developmental tiers according to Kendler's model (childhood, early adolescence, late adolescence, adulthood, past-year). Hierarchical logistic regression models were built to predict the risk of smoking initiation and the risk of ND, given initiation. The continuation ratio (CR) was tested by ordinal logistic regression to examine whether the impact of the predictors was the same on smoking initiation or ND. Results The final models highlighted the importance of different tiers for each outcome. The CR identified substantial differences in the predictors of smoking initiation versus ND. Childhood tier appears to be more determinant for smoking initiation while the effect of more distal tiers (i.e. childhood and early adolescence) was tempered by more proximal ones (i.e. late adolescence, adulthood and past-year) in ND, with few sex differences. Conclusions The differential effect of some predictors on each outcome shows the complexity of pathways from smoking initiation to ND. While some risk factors may be shared, others impact only at one stage or have even an inverse effect. An adaptation of Kendler's developmental model for major depression showed high predictive power for smoking initiation and ND.
    Drug and Alcohol Dependence 09/2014; 144. DOI:10.1016/j.drugalcdep.2014.09.002 · 3.42 Impact Factor
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    • "Alcohol is widely abused for its euphoric and sedative effects, and dependence on alcohol (alcoholism) has tremendous costs to afflicted individuals and society. A multitude of twin and adoption studies demonstrate that risk for alcoholism is 50–65% genetically determined (Kendler et al. 2009; Palmer et al. 2012; Reich et al. 1999). Unfortunately, genetic determinants of risk remain largely unknown, hindering effective prevention and treatment of dependent individuals. "
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    ABSTRACT: Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference, we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral-mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared to control mice delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol enhanced convulsions differed between Mpdz shRNA and control animals, indicating that Mpdz expression in the caudolateral substantia nigra pars reticulata does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNA interference analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the caudolateral substantia nigra pars reticulata is crucially involved in risk for alcohol withdrawal.
    Genes Brain and Behavior 08/2014; 13(8). DOI:10.1111/gbb.12171 · 3.66 Impact Factor
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