Using Dimensional Models of Externalizing Psychopathology to Aid in Gene Identification

Dick, Danielle M.; Alıev, Fazil; Wang, Jen C.; Grucza, Richard A.; Schuckit, Marc A.; Kuperman, Samuel; Kramer, John; Hinrichs, Anthony L.; Bertelsen, Sarah; Budde, John; Hesselbrock, Victor; Porjesz, Bernice; Edenberg, Howard J.; Bierut, Laura J.; Goate, Alison

doi:10.1001/archpsyc.65.3.310

Cited by 134 publications

(116 citation statements)

References 69 publications

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“…Studies support over-transmission of the risk variants of various genes in individuals with different psychiatric disorders. For example, the muscarinic acetylcholine receptor M 2 gene (CHRM2) is involved in the stress response system among other functions (e.g., attention, learning, memory and cognition) and has been linked to alcohol and drug dependence (Wang et al, 2004), a general composite externalizing factor (Dick et al, 2008), and depression (Comings et al, 2002). In addition, findings regarding genes involved in SUDs (e.g., related to dopamine functioning) have also been implicated in BD traits like impulsivity and risk taking (Hiroi & Agatsuma, 2005;Kreek, Nielsen, Butelman, & LaForge, 2005) and the association between neuroticism and SUDs (Ellis et al, 2011).…”

Section: Molecular Genetics: Identifying Genesmentioning

confidence: 99%

An Integrative Common Liabilities Model for the Comorbidity of Substance Use Disorders with Externalizing and Internalizing Disorders

Tully

Iacono

2014

Oxford Handbooks Online

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This paper presents an integrative research-derived model to explain comorbidity among SUDs, externalizing disorders, and internalizing disorders. This hierarchical model is based on phenotypic covariance among the disorders and latent common genetic liability. At the highest level of the hierarchy, general genetically-influenced biological dispositions to negative emotionality and behavioral disinhibition each give rise to spectra of related personality traits, cognitive processes, behavioral tendencies, and psychopathology that account for the pattern of co-occurrence among mental disorders. At the lowest level of the hierarchy, disorder-specific genetic and environmental effects explain the presence of some and not other disorders associated with a given general liability. Interplay between the general liabilities and both other genes and environmental factors throughout development affect the likelihood of developing specific mental disorders.

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Section: Molecular Genetics: Identifying Genesmentioning

confidence: 99%

An Integrative Common Liabilities Model for the Comorbidity of Substance Use Disorders with Externalizing and Internalizing Disorders

Tully

Iacono

2014

Oxford Handbooks Online

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“…In addition to the effects of cocaine mediated by dopaminergic efflux, cocaine itself has direct effects on M 1 and M 2 (Flynn et al, 1992b;Karpen and Hess, 1986;Sharkey et al, 1988b) receptors. In human studies, polymorphisms of the mAChR M2 gene (CHRM2) have recently been shown to be involved in a general externalizing phenotype predictive of substance-use disorders (Dick et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Adinoff

Devous

Williams

et al. 2010

Neuropsychopharmacol

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Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1-to 6-week abstinent, cocaine-(and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (po0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

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“…These include DAT1 (Sharp et al, 2009;van der Zwaluw et al, 2009), GABRA2 (Dick et al, 2006;Edenberg et al, 2004), CHRM2 (Dick et al, 2008), and CDH13 Treutlein et al, 2009). Furthermore, Dick and colleagues (2010a) identifi ed 23 genes on chromosome 2 that harbor markers associated with a "behavioral disinhibition" phenotype in which individuals were considered "affected" if they were alcohol dependent and had either met criteria for CD or had attempted suicide.…”

mentioning

confidence: 99%

Twin Study of the Relationship Between Adolescent Attention-Deficit/Hyperactivity Disorder and Adult Alcohol Dependence

Edwards

Kendler

2012

J. Stud. Alcohol Drugs

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ABSTRACT. Objective: Adolescent problem behaviors such as conduct disorder and attention-defi cit/hyperactivity disorder (ADHD) are often associated with alcohol problems in adulthood, particularly alcohol dependence. This association is partly a result of shared genetic liability. However, it is unclear whether ADHD, or an ADHD subtype, shares genetic infl uences with alcohol dependence beyond those also shared by conduct disorder. Method: We evaluated phenotypic associations between adolescent conduct disorder and ADHD phenotypes with adult alcohol dependence in a population-based sample of adult male twins (N = 1,774). We then assessed genetic and environmental relationships among phenotypes using structural equation modeling. Results: Individually, conduct disorder and each ADHD factor were associated with adult alcohol dependence. Results from twin modeling indicate that a genetic factor common to conduct disorder and ADHD also loads strongly onto alcohol dependence. Even after controlling for genetic factors shared with conduct disorder and other ADHD factors, the hyperactivity component of ADHD shared signifi cant residual genetic infl uences with alcohol dependence. Conclusions: Most of the genetically mediated association between adolescent ADHD and adult alcohol dependence is shared with conduct disorder, refl ecting a generalized risk to externalizing behaviors. The signifi cant residual genetic covariance between the ADHD factor hyperactivity/impulsivity and alcohol dependence implies that impulsive behaviors less destructive/harmful than those manifested by conduct disorder can be indicative of genetic risk for adult alcohol dependence. However, the ADHD factors inattention and forgetfulness are not uniquely predictive of genetic/environmental risk for alcohol dependence. (J. Stud. Alcohol Drugs, 73, 185-194, 2012)

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Using Dimensional Models of Externalizing Psychopathology to Aid in Gene Identification

Abstract: Broader conceptualizations of psychiatric disorders, such as studying a spectrum of externalizing psychopathology, may aid in identifying susceptibility genes and understanding the pathways through which genetic factors affect vulnerability for a variety of poor outcomes.

Cited by 134 publications

References 69 publications

An Integrative Common Liabilities Model for the Comorbidity of Substance Use Disorders with Externalizing and Internalizing Disorders

An Integrative Common Liabilities Model for the Comorbidity of Substance Use Disorders with Externalizing and Internalizing Disorders

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Twin Study of the Relationship Between Adolescent Attention-Deficit/Hyperactivity Disorder and Adult Alcohol Dependence

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