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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

a The susceptibility haplotype encompasses exons 4–19 of LPHN3, and contains important functional domains and variable splicing sites for isoforms of the gene. There are not other genes annotated over the region spanned by the susceptibility haplotype. b General structure of latrophilins. The long extracellular region contains four domains: a SUEL LECTIN domain, a region homologous to olfactomedins and myocilin, a homology region (HR) with BAI1-3, and a cysteine-rich GPCR proteolysis site (gps). With modifications from Arcos-Burgos et al. (2010)
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Fig6: a The susceptibility haplotype encompasses exons 4–19 of LPHN3, and contains important functional domains and variable splicing sites for isoforms of the gene. There are not other genes annotated over the region spanned by the susceptibility haplotype. b General structure of latrophilins. The long extracellular region contains four domains: a SUEL LECTIN domain, a region homologous to olfactomedins and myocilin, a homology region (HR) with BAI1-3, and a cysteine-rich GPCR proteolysis site (gps). With modifications from Arcos-Burgos et al. (2010)

Mentions: The region of association was located at 62.4–62.7 Mb (UCSC coordinates) on 4q within exons 4 through 19 of the Latrophilin3 gene (LPHN3) (Arcos-Burgos et al. 2010). Latrophilin3 is a member of the latrophilin (LPHN) subfamily of G-protein coupled receptors (GPCRs). Genes encoding the GPCRs, such as DRD4 and DRD5, have also been shown to be associated with ADHD (Arcos-Burgos et al. 2010) (Fig. 6a).Fig. 6


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)

a The susceptibility haplotype encompasses exons 4–19 of LPHN3, and contains important functional domains and variable splicing sites for isoforms of the gene. There are not other genes annotated over the region spanned by the susceptibility haplotype. b General structure of latrophilins. The long extracellular region contains four domains: a SUEL LECTIN domain, a region homologous to olfactomedins and myocilin, a homology region (HR) with BAI1-3, and a cysteine-rich GPCR proteolysis site (gps). With modifications from Arcos-Burgos et al. (2010)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351604&req=5

Fig6: a The susceptibility haplotype encompasses exons 4–19 of LPHN3, and contains important functional domains and variable splicing sites for isoforms of the gene. There are not other genes annotated over the region spanned by the susceptibility haplotype. b General structure of latrophilins. The long extracellular region contains four domains: a SUEL LECTIN domain, a region homologous to olfactomedins and myocilin, a homology region (HR) with BAI1-3, and a cysteine-rich GPCR proteolysis site (gps). With modifications from Arcos-Burgos et al. (2010)
Mentions: The region of association was located at 62.4–62.7 Mb (UCSC coordinates) on 4q within exons 4 through 19 of the Latrophilin3 gene (LPHN3) (Arcos-Burgos et al. 2010). Latrophilin3 is a member of the latrophilin (LPHN) subfamily of G-protein coupled receptors (GPCRs). Genes encoding the GPCRs, such as DRD4 and DRD5, have also been shown to be associated with ADHD (Arcos-Burgos et al. 2010) (Fig. 6a).Fig. 6

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