The Structure of Genetic and Environmental Risk Factors for Common Psychiatric and Substance Use Disorders in Men and Women

Virginia Institute for Psychiatry and Behavioral Genetics and the Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0126, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 10/2003; 60(9):929-37. DOI: 10.1001/archpsyc.60.9.929
Source: PubMed


Patterns of comorbidity suggest that the common psychiatric and substance use syndromes may be divisible into 2 broad groups of internalizing and externalizing disorders. We do not know how genetic and environmental risk factors contribute to this pattern of comorbidity or whether the etiologic structure of these groups differ in men and women.
Lifetime diagnoses for 10 psychiatric syndromes were obtained at a personal interview in more than 5600 members of male-male and female-female twin pairs ascertained from a population-based registry. Multivariate twin modeling was performed using the program Mx.
We first fit models to the following 7 syndromes: major depression, generalized anxiety disorder, phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. The full model, which could be constrained to equality in male and female subjects, identified 2 genetic factors. The first had strongest loadings on alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder; the second, on major depression, generalized anxiety disorder, and phobia. Alcohol dependence and drug abuse/dependence had substantial disorder-specific genetic risk factors. Shared environmental factors were most pronounced for conduct disorder and adult antisocial behavior. No clear internalizing/externalizing structure was seen for the unique environmental common factors. We then fit models to 5 internalizing syndromes. The full model, which could also be constrained to equality in men and women, revealed one genetic factor loading most heavily on major depression and generalized anxiety disorder and another loading most strongly on animal and situational phobia.
The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar. Genetic risk factors predispose to 2 broad groups of internalizing and externalizing disorders. Within the internalizing disorders, 2 genetic factors are seen that predispose to disorders dominated by anxious-misery and fear. Substance use disorders have disorder-specific genetic risks. The externalizing disorders of conduct disorder and adult antisocial behavior are significantly influenced by the shared environment. The pattern of lifetime comorbidity of common psychiatric and substance use disorders results largely from the effects of genetic risk factors.

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    • "However, apart from the protective effects associated with polymorphisms in the genes encoding the alcohol-metabolizing enzymes, alcohol dehydrogenase and acetaldehyde dehydrogenase , no other robust or replicable findings have been identified. Alcohol dependence frequently co-occurs with psychiatric disorders and drug dependence (Deegenhardt et al., 2001; Wagner and Anthony, 2002; Kendler et al., 2003), as well as with alcohol-related comorbidities such as liver injury. All of these phenotypic traits are likely influenced by genotype and hence act as confounders in genetic studies on alcohol dependence (Tian et al., 2010; Edwards et al., 2012; Sharp et al., 2014). "
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    • "Underlying genetic factors may in part explain this difference. There is stronger evidence for genetic pleiotropy of substance use and externalizing problems than there is for substance use and internalizing psychopathology (Edwards et al. 2011; Hicks et al. 2011; Kendler et al. 2003; Stephens et al. 2012) and thus even without any causal effects of prenatal smoking, an association of maternal smoking and externalizing offspring behavior is expected as mothers pass on their risk genes to their offspring. The association of prenatal smoking with offspring externalizing problems may be further amplified by interactions between offspring Table 3 P values in the regression of the dependent phenotype (column 1) on the covariates (columns 2–6) and the predictor of interest (''maternal vs. paternal SDP''; column 11) "
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    • "with AD and general substance use disorders (Krueger et al. 2002; Kendler et al. 2003b), but not all in the same analysis]; (b) extended Hicks and colleagues analysis of adolescents (aged 16–19 years; Hicks et al. 2011), which could yield different patterns of overlap; (c) set to missing the data from individuals who had not initiated a substance and hence had unknown genetic liability. Our results are consistent with previous reports (Fu et al. 2002; Kendler et al. 2003b; Button et al. 2006; Hicks et al. 2011) showing that alcohol and drug dependence tend to share an appreciable proportion of their genetic liability with conduct and antisocial personality disorder, and further demonstrating that similar effects extend to ND and to substance use disorders contingent on initiation. The overall structure of genetic overlap (see Fig. 1) is also broadly consistent with numerous twin studies of adolescent and adult populations indexing a general liability factor underlying a host of externalizing disorders, including conduct disorder , substance use disorders and also impulsivity and non-substance-related disinhibition (Krueger et al. 2002; Hicks et al. 2011). "
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