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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

Results from a formal network analysis using the ANKK1, TTC12, DRD2, NCAM1, LPHN3, and CDH13 genes in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization and protein domain similarity. These selected genes were significantly replicated as being either associated and/or linked to ADHD, disruptive behaviors and SUD. Networks related to pathways involved in processes such as axon guidance, regulation of synaptic transmission and regulation of transmission of nerve impulse were overrepresented. For more information see Tables 2 and 3
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Fig7: Results from a formal network analysis using the ANKK1, TTC12, DRD2, NCAM1, LPHN3, and CDH13 genes in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization and protein domain similarity. These selected genes were significantly replicated as being either associated and/or linked to ADHD, disruptive behaviors and SUD. Networks related to pathways involved in processes such as axon guidance, regulation of synaptic transmission and regulation of transmission of nerve impulse were overrepresented. For more information see Tables 2 and 3

Mentions: In order to contrast the main hypothesis of the manuscript, i.e., the existence of a network of genes underlying these complex phenotypes, we performed a formal network analysis with the LPHN3, NCAM1, TTC12, ANKK1, DRD2, and CDH13 genes, a set of significantly replicated genes either associated and/or linked to ADHD, disruptive behaviors, and SUD (Table 1). In addition, in order to detect significantly enriched gene categories within this set of genes, we performed analyses with the GeneMANIA Pathway Analysis software (http://genemania.org/). GeneMANIA uses a large set of available functional association data for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found additional genes in pathways (Table 2 and Fig. 7), as well as functions that frame these apparently unrelated genes to statistically significant gene ontology (GO) networks related to pathways, such as axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse, among others (Table 3).Table 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)

Results from a formal network analysis using the ANKK1, TTC12, DRD2, NCAM1, LPHN3, and CDH13 genes in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization and protein domain similarity. These selected genes were significantly replicated as being either associated and/or linked to ADHD, disruptive behaviors and SUD. Networks related to pathways involved in processes such as axon guidance, regulation of synaptic transmission and regulation of transmission of nerve impulse were overrepresented. For more information see Tables 2 and 3
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Related In: Results  -  Collection

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

Fig7: Results from a formal network analysis using the ANKK1, TTC12, DRD2, NCAM1, LPHN3, and CDH13 genes in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization and protein domain similarity. These selected genes were significantly replicated as being either associated and/or linked to ADHD, disruptive behaviors and SUD. Networks related to pathways involved in processes such as axon guidance, regulation of synaptic transmission and regulation of transmission of nerve impulse were overrepresented. For more information see Tables 2 and 3
Mentions: In order to contrast the main hypothesis of the manuscript, i.e., the existence of a network of genes underlying these complex phenotypes, we performed a formal network analysis with the LPHN3, NCAM1, TTC12, ANKK1, DRD2, and CDH13 genes, a set of significantly replicated genes either associated and/or linked to ADHD, disruptive behaviors, and SUD (Table 1). In addition, in order to detect significantly enriched gene categories within this set of genes, we performed analyses with the GeneMANIA Pathway Analysis software (http://genemania.org/). GeneMANIA uses a large set of available functional association data for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found additional genes in pathways (Table 2 and Fig. 7), as well as functions that frame these apparently unrelated genes to statistically significant gene ontology (GO) networks related to pathways, such as axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse, among others (Table 3).Table 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