Molecular genetics of addiction and related heritable phenotypes: Genome-wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects

Molecular Neurobiology Branch, National Institutes of Health (NIH), Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA), Baltimore, MD 21224, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.31). 11/2008; 1141:318-81. DOI: 10.1196/annals.1441.018
Source: PubMed

ABSTRACT Genome-wide association (GWA) can elucidate molecular genetic bases for human individual differences in complex phenotypes that include vulnerability to addiction. Here, we review (a) evidence that supports polygenic models with (at least) modest heterogeneity for the genetic architectures of addiction and several related phenotypes; (b) technical and ethical aspects of importance for understanding GWA data, including genotyping in individual samples versus DNA pools, analytic approaches, power estimation, and ethical issues in genotyping individuals with illegal behaviors; (c) the samples and the data that shape our current understanding of the molecular genetics of individual differences in vulnerability to substance dependence and related phenotypes; (d) overlaps between GWA data sets for dependence on different substances; and (e) overlaps between GWA data for addictions versus other heritable, brain-based phenotypes that include bipolar disorder, cognitive ability, frontal lobe brain volume, the ability to successfully quit smoking, neuroticism, and Alzheimer's disease. These convergent results identify potential targets for drugs that might modify addictions and play roles in these other phenotypes. They add to evidence that individual differences in the quality and quantity of brain connections make pleiotropic contributions to individual differences in vulnerability to addictions and to related brain disorders and phenotypes. A "connectivity constellation" of brain phenotypes and disorders appears to receive substantial pathogenic contributions from individual differences in a constellation of genes whose variants provide individual differences in the specification of brain connectivities during development and in adulthood. Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes.

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Available from: Qing-Rong Liu, Jul 28, 2015
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    • "Based on this analysis, and consistent with the high comorbidity of drug dependence with other psychiatric disorders , it was suggested that GWAS for a number of psychiatric conditions will identify overlapping sets of genes with pleiotropic influences (Uhl et al., 2008b). This was confirmed for substance dependence and bipolar disorder in one analysis (Johnson et al., 2009) and is discussed in detail in Uhl et al. (2008b). Furthermore, analysis of the genes associated with smoking cessation identified a plausible Bayesian network which could not be produced by random selection of SNPs (Uhl et al., 2010). "
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    ABSTRACT: Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS.
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    • "We hypothesized that trans-synaptic interactions may contribute to the structural synaptic changes that occur in response to drugs of abuse. Although SynCAM-encoding genes have not yet been linked to addiction-related behaviors, genome-wide association studies support roles of adhesion proteins (Uhl et al, 2008). This is consistent with the association of neurexin polymorphisms with substance abuse (Hishimoto et al, 2007; Stoltenberg et al, 2011). "
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    • "Moreover, the association of CDH13 appears not to be limited to ADHD but refers to ADHD-related traits also, such as the personality dimension ''extraversion'' (Terracciano et al., 2010). Findings from other GWA studies also suggest an involvement of CDH13 in the susceptibility to substance abuse and alcohol dependence (Uhl et al., 2008a, 2008b; Treutlein et al., 2009), conditions often co-morbid with ADHD, as well as depressive syndromes co-morbid with alcohol dependence (Edwards et al., 2012). In addition, affective disorders have directly been related to CDH13: its expression appears to be up-regulated in the amygdala of patients with major depressive disorder as well as in corresponding brain areas in an unpredictable chronic mild stress (UCMS) rodent model of depression (Sibille et al., 2009). "
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