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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Available from: Michael C Neale, Oct 13, 2015
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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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    ABSTRACT: Background: The interpretation of genetic studies on alcohol dependence may be confounded by the co-occurrence of substance dependence, psychiatric disorders and alcohol-related comorbidities, for example, cirrhosis. Significant single-marker and haplotypic associations between polymorphisms in the zinc finger gene, ZNF699, and alcohol dependence were reported in the Irish Affected Sib Pair Study of Alcohol Dependence population, of whom one-third had co-occurring substance dependence and 80% had identified psychiatric comorbidity. The aim of this study was to explore variant ZNF699 associations with alcohol dependence while exercising controls for potential confounders. Methods: The study population was comprised of 1449 alcohol-dependent cases and 1283 population controls; all were of British or Irish ancestry. None of the cases had a history of dependence on other substances, and the frequency of comorbid depression was low. A separate, ancestry-matched cohort of 196 opioid-dependent cases was also included. Genotyping for the four previously identified SNPs of interest in ZNF699 was performed using K-Biosciences Competitive Allele Specific PCR. Results: No single-marker associations were found between polymorphisms in ZNF699 and alcohol dependence per se. A significant allelic association was found between rs7254880 in ZNF699 and alcohol-related cirrhosis (n=292), using cases with no biopsy evidence of liver disease (n=314) as controls (P=0.013). Significant allelic associations were also found between rs12460279 (P=0.028), rs7252865 (P=0.012) and rs10854142 (P=0.016) in ZNF699 and opioid dependence. Conclusion: Phenotypic variation in study populations may contribute towards the nonreplication of genetic association studies on alcohol dependence; controls for recognised confounding variables should be exercised whenever possible.
    Psychiatric genetics 09/2015; DOI:10.1097/YPG.0000000000000105 · 1.94 Impact Factor
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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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    Behavior Genetics 09/2015; DOI:10.1007/s10519-015-9738-2 · 3.21 Impact Factor
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    • "The present study is the first, to our knowledge, to test age invariance in the internalizing-externalizing liability model of disorder comorbidity using a wide range of categorical DSM-IV disorders as indicators in seven age groups. Our results indicate that this model, well established for the general adult population (Blanco et al., 2013; Eaton et al., 2012; Insel et al., 2010; Kendler et al., 2003; Kessler et al., 2011; Kotov et al., 2011; Krueger et al., 2003, 1998; Vollebergh et al., 2001), holds for the older population , and suggests that these dimensions of psychopathology remain invariant from early to late adulthood. These results also suggest that psychiatric disorders in older adults are not mere the consequence of aging, but rather reflect the continuity of shared psychological and biological processes underlying these broad psychopathological dimensions that remain active throughout adult life. "
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    ABSTRACT: Recent theories have proposed a metastructure that organizes related mental disorders into broad dimensions of psychopathology (i.e., internalizing and externalizing dimensions). Prevalence rates of most mental disorders, when examined independently, are substantially lower in older than in younger adults, which may affect this metastructure. Within a nationally representative sample, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N = 43,093), we developed a dimensional liability model of common psychiatric disorders to clarify whether aging affects specific disorders or general dimensions of psychopathology. Significant age differences existed across age groups (18-24, 25-34, 35-44, 45-54, 55-64, 65-75 and 75+), such that older adults showed lower prevalence rates of most disorders compared to younger adults. We next investigated patterns of disorder comorbidity for past-year psychiatric disorders and found that a distress-fear-externalizing liability model fit the data well. This model was age-group invariant and indicated that the observed lower prevalence of mental disorders with advancing age originates from lower average means on externalizing and internalizing liability dimensions. This unifying dimensional liability model of age and mental disorder comorbidity can help inform the role of aging on mental disorder prevalence for research and intervention efforts, and service planning for the impending crisis in geriatric mental health. Copyright © 2015 Elsevier Ltd. All rights reserved.
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