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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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Model-based and model-free linkage analyses in extended and multigenerational Paisa families found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11. These results were compatible with the presence of epistasis and pleiotropy in replication studies, suggesting that these loci harbor ADHD susceptibility genes. With modifications from Arcos-Burgos et al. (2004b)
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Fig3: Model-based and model-free linkage analyses in extended and multigenerational Paisa families found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11. These results were compatible with the presence of epistasis and pleiotropy in replication studies, suggesting that these loci harbor ADHD susceptibility genes. With modifications from Arcos-Burgos et al. (2004b)

Mentions: We applied model-based and model-free linkage analyses and the pedigree disequilibrium test (PDT)(Martin et al. 2000) to genome-wide scan genotype data obtained for the Paisa families and found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families (Arcos-Burgos et al. 2004b). Fine mapping of these regions in the combined families resulted in significant linkage at chromosomes 4q13.2 (two-point allele sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele sharing LOD score from LODPAL = 5.77 at D11S1998, multipoint NPL −log(P) = 5.49 at ~128 cM) and 17p11 (multipoint NPL −log(P) >12 at ~12 cM, multipoint MLS = 2.48 (α = 0.10) at ~12 cM, two-point allele sharing LOD score from LODPAL = 3.73 at D17S1159). In addition, suggestive linkage at chromosome 8q11.23 was found (combined two-point NPL −log(P) >3.0 at D8S2332) (Arcos-Burgos et al. 2004b). Several of these regions were novel (4q13.2, 5q33.3, and 8q11.23) while others strongly replicated published loci (11q22 and 17p11). In summary, we identified linkage to the same genomic regions in different pedigrees, and to several genomic regions in specific pedigrees. These findings are compatible with the effects of epistasis and pleiotropy, respectively. The strong concordance between different analytical methods of linkage and the replication of data between two independent studies suggest that these loci harbor ADHD susceptibility genes (Fig. 3) (Arcos-Burgos et al. 2004b).Fig. 3


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)

Model-based and model-free linkage analyses in extended and multigenerational Paisa families found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11. These results were compatible with the presence of epistasis and pleiotropy in replication studies, suggesting that these loci harbor ADHD susceptibility genes. With modifications from Arcos-Burgos et al. (2004b)
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Model-based and model-free linkage analyses in extended and multigenerational Paisa families found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11. These results were compatible with the presence of epistasis and pleiotropy in replication studies, suggesting that these loci harbor ADHD susceptibility genes. With modifications from Arcos-Burgos et al. (2004b)
Mentions: We applied model-based and model-free linkage analyses and the pedigree disequilibrium test (PDT)(Martin et al. 2000) to genome-wide scan genotype data obtained for the Paisa families and found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families (Arcos-Burgos et al. 2004b). Fine mapping of these regions in the combined families resulted in significant linkage at chromosomes 4q13.2 (two-point allele sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele sharing LOD score from LODPAL = 5.77 at D11S1998, multipoint NPL −log(P) = 5.49 at ~128 cM) and 17p11 (multipoint NPL −log(P) >12 at ~12 cM, multipoint MLS = 2.48 (α = 0.10) at ~12 cM, two-point allele sharing LOD score from LODPAL = 3.73 at D17S1159). In addition, suggestive linkage at chromosome 8q11.23 was found (combined two-point NPL −log(P) >3.0 at D8S2332) (Arcos-Burgos et al. 2004b). Several of these regions were novel (4q13.2, 5q33.3, and 8q11.23) while others strongly replicated published loci (11q22 and 17p11). In summary, we identified linkage to the same genomic regions in different pedigrees, and to several genomic regions in specific pedigrees. These findings are compatible with the effects of epistasis and pleiotropy, respectively. The strong concordance between different analytical methods of linkage and the replication of data between two independent studies suggest that these loci harbor ADHD susceptibility genes (Fig. 3) (Arcos-Burgos et al. 2004b).Fig. 3

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