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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

ADHD mapping by LD using cladistic analyses with closely spaced SNP markers across the critical region in 137 additional nuclear families reveals an area of association between 62.4 and 62.7 Mb in chromosome 4 (in red). With modifications from Arcos-Burgos et al. (2010)
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Fig5: ADHD mapping by LD using cladistic analyses with closely spaced SNP markers across the critical region in 137 additional nuclear families reveals an area of association between 62.4 and 62.7 Mb in chromosome 4 (in red). With modifications from Arcos-Burgos et al. (2010)

Mentions: Using the integration of statistical and functional approaches, we discovered a novel gene that segregates with ADHD and contributes to disease susceptibility; this gene is harbored in the chromosome 4q region previously found to be linked to ADHD (Fig. 5). The application of fine mapping to these linked families sharpened the linkage signal and revealed new meiotic recombination events in individuals with ADHD, which further narrowed the minimal critical region with the gene to ~20 Mb (Arcos-Burgos et al. 2010) (Fig. 5). Fine-scale genetic association was conducted in nuclear and large multigenerational Paisa families. Areas of interest included those that were gene-rich or that included potential candidate genes, and were covered at a higher density (Arcos-Burgos et al. 2010). Using family-based association strategies and haplotype-based cladistic analysis, a significant area of association with ADHD was then defined by the single nucleotide polymorphic (SNP) markers rs1901223 and rs1355368 (P = 3.1 × 10−3, marker-based; P = 2.7 × 10−5, haplotype based) (Arcos-Burgos et al. 2010) (Fig. 5).Fig. 5


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)

ADHD mapping by LD using cladistic analyses with closely spaced SNP markers across the critical region in 137 additional nuclear families reveals an area of association between 62.4 and 62.7 Mb in chromosome 4 (in red). With modifications from Arcos-Burgos et al. (2010)
© Copyright Policy
Related In: Results  -  Collection

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

Fig5: ADHD mapping by LD using cladistic analyses with closely spaced SNP markers across the critical region in 137 additional nuclear families reveals an area of association between 62.4 and 62.7 Mb in chromosome 4 (in red). With modifications from Arcos-Burgos et al. (2010)
Mentions: Using the integration of statistical and functional approaches, we discovered a novel gene that segregates with ADHD and contributes to disease susceptibility; this gene is harbored in the chromosome 4q region previously found to be linked to ADHD (Fig. 5). The application of fine mapping to these linked families sharpened the linkage signal and revealed new meiotic recombination events in individuals with ADHD, which further narrowed the minimal critical region with the gene to ~20 Mb (Arcos-Burgos et al. 2010) (Fig. 5). Fine-scale genetic association was conducted in nuclear and large multigenerational Paisa families. Areas of interest included those that were gene-rich or that included potential candidate genes, and were covered at a higher density (Arcos-Burgos et al. 2010). Using family-based association strategies and haplotype-based cladistic analysis, a significant area of association with ADHD was then defined by the single nucleotide polymorphic (SNP) markers rs1901223 and rs1355368 (P = 3.1 × 10−3, marker-based; P = 2.7 × 10−5, haplotype based) (Arcos-Burgos et al. 2010) (Fig. 5).Fig. 5

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