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

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.

Fig. 1

Physiopathological and psychopathological mechanisms, and genetic factors shared by attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), oppositional defiant disorder (ODD) and substance-use disorder (SUD)

Fig. 2

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)

Fig. 3

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)

Fig. 4

Linkage- and association-based genome scans identified loci containing common allelic variants contributing to SUD and to some psychiatric conditions

Fig. 5

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)

Fig. 6

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)

Fig. 7

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