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A common genetic network underlies substance use disorders and disruptive or externalizing disorders.

Arcos-Burgos M, Vélez JI, Solomon BD, Muenke M - Hum. Genet. (2012)

Bottom Line: Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors.Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment.We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA. arcosburgosm@mail.nih.gov

ABSTRACT
Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors. Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment. These data have been depicted in our studies by extended pedigrees, where ADHD, externalizing symptoms, and SUD segregate and co-segregate. Finally, we applied here a new formal network analysis using the set of significantly replicated genes that have been shown to be either associated and/or linked to ADHD, disruptive behaviors, and SUD in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented. In summary, we provide compiled evidence of complex networks of genotypes underlying a wide phenotype that involves SUD and externalizing disorders.

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Related in: MedlinePlus

An extended pedigree demonstrating ADHD, externalizing symptoms, and associated conditions including nicotine, dependence and alcohol abuse and/or dependence. With modifications from Palacio et al. (2004)
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Fig2: An extended pedigree demonstrating ADHD, externalizing symptoms, and associated conditions including nicotine, dependence and alcohol abuse and/or dependence. With modifications from Palacio et al. (2004)

Mentions: Furthermore, we show that same genetic variants, harbored at different genes (loci), may be associated with different syndromes (Arcos-Burgos and Muenke 2010; Jain et al. 2007) and, in particular cases, non-linear interactions between these variants (epistasis) correlate with the specific phenotype, the severity of that phenotype, the long-term clinical outcome, and response to treatment (Jain et al. 2011). In addition, we will demonstrate that in extended pedigrees, ADHD, externalizing symptoms, and SUD can all be present simultaneously in one individual, and also, that different members of a single pedigree can exhibit variable combinations of these syndromes (Fig. 2). Finally, by applying formal network analysis, we will show that these apparently unrelated genes are overrepresented by statistically significant gene ontology (GO) networks related to pathways such as those that involve axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse.Fig. 2


A common genetic network underlies substance use disorders and disruptive or externalizing disorders.

Arcos-Burgos M, Vélez JI, Solomon BD, Muenke M - Hum. Genet. (2012)

An extended pedigree demonstrating ADHD, externalizing symptoms, and associated conditions including nicotine, dependence and alcohol abuse and/or dependence. With modifications from Palacio et al. (2004)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351604&req=5

Fig2: An extended pedigree demonstrating ADHD, externalizing symptoms, and associated conditions including nicotine, dependence and alcohol abuse and/or dependence. With modifications from Palacio et al. (2004)
Mentions: Furthermore, we show that same genetic variants, harbored at different genes (loci), may be associated with different syndromes (Arcos-Burgos and Muenke 2010; Jain et al. 2007) and, in particular cases, non-linear interactions between these variants (epistasis) correlate with the specific phenotype, the severity of that phenotype, the long-term clinical outcome, and response to treatment (Jain et al. 2011). In addition, we will demonstrate that in extended pedigrees, ADHD, externalizing symptoms, and SUD can all be present simultaneously in one individual, and also, that different members of a single pedigree can exhibit variable combinations of these syndromes (Fig. 2). Finally, by applying formal network analysis, we will show that these apparently unrelated genes are overrepresented by statistically significant gene ontology (GO) networks related to pathways such as those that involve axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse.Fig. 2

Bottom Line: Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors.Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment.We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA. arcosburgosm@mail.nih.gov

ABSTRACT
Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors. Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment. These data have been depicted in our studies by extended pedigrees, where ADHD, externalizing symptoms, and SUD segregate and co-segregate. Finally, we applied here a new formal network analysis using the set of significantly replicated genes that have been shown to be either associated and/or linked to ADHD, disruptive behaviors, and SUD in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented. In summary, we provide compiled evidence of complex networks of genotypes underlying a wide phenotype that involves SUD and externalizing disorders.

Show MeSH
Related in: MedlinePlus