Uhl GR, Drgon T, Johnson C, Li CY, Contoreggi C, Hess J et al. Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify ‘connectivity constellation’ and drug target genes with pleiotropic effects. Ann N Y Acad Sci 1141: 318-381

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: 4.38). 11/2008; 1141:318-81. DOI: 10.1196/annals.1441.018
Source: PubMed


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.

Download full-text


Available from: Qing-Rong Liu, Oct 04, 2015
82 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Pharmacology [?] Therapeutics 07/2013; 140(3). DOI:10.1016/j.pharmthera.2013.07.006 · 9.72 Impact Factor
  • Source
    • "Yet it is also influenced by an individual’s desire to participate in genetic research. Some patients with various psychiatric, genetically-based disorders are more inclined than others to seek treatment and to volunteer for clinical studies [17]. While the grounds for this distinctive behaviour are not clear, the behaviour itself may be influenced by a variety of reasons. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Next Generation Sequencing (NGS) is expected to help find the elusive, causative genetic defects associated with Bipolar Disorder (BD). This article identifies the importance of NGS and further analyses the social and ethical implications of this approach when used in research projects studying BD, as well as other psychiatric ailments, with a view to ensuring the protection of research participants. Methods We performed a systematic review of studies through PubMed, followed by a manual search through the titles and abstracts of original articles, including the reviews, commentaries and letters published in the last five years and dealing with the ethical and social issues raised by NGS technologies and genomics studies of mental disorders, especially BD. A total of 217 studies contributed to identify the themes discussed herein. Results The amount of information generated by NGS renders individuals suffering from BD particularly vulnerable, and increases the need for educational support throughout the consent process, and, subsequently, of genetic counselling, when communicating individual research results and incidental findings to them. Our results highlight the importance and difficulty of respecting participants’ autonomy while avoiding any therapeutic misconception. We also analysed the need for specific regulations on the use and communication of incidental findings, as well as the increasing influence of NGS in health care. Conclusions Shared efforts on the part of researchers and their institutions, Research Ethics Boards as well as participants’ representatives are needed to delineate a tailored consent process so as to better protect research participants. However, health care professionals involved in BD care and treatment need to first determine the scientific validity and clinical utility of NGS-generated findings, and thereafter their prevention and treatment significance.
    BMC Medical Ethics 12/2012; 13(1):36. DOI:10.1186/1472-6939-13-36 · 1.50 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Drugs of abuse have acute and persistent effects on synapse structure and addiction-related behaviors. Trans-synaptic interactions can control synapse development, and synaptic cell adhesion molecule (SynCAM) proteins (also named nectin-like molecules) are immunoglobulin adhesion proteins that span the synaptic cleft and induce excitatory synapses. Our studies now reveal that the loss of SynCAM 1 in knockout (KO) mice reduces excitatory synapse number in nucleus accumbens (NAc). SynCAM 1 additionally contributes to the structural remodeling of NAc synapses in response to the psychostimulant cocaine. Specifically, we find that cocaine administration increases the density of stubby spines on medium spiny neurons in NAc, and that maintaining this increase requires SynCAM 1. Furthermore, mushroom-type spines on these neurons are structurally more plastic when SynCAM 1 is absent, and challenging drug-withdrawn mice with cocaine shortens these spines in SynCAM 1 KO mice. These effects are correlated with changes on the behavioral level, where SynCAM 1 contributes to the psychostimulant effects of cocaine as measured after acute and repeated administration, and in drug-withdrawn mice. Together, our results provide evidence that the loss of a synapse-organizing adhesion molecule can modulate cocaine effects on spine structures in NAc and increases vulnerability to the behavioral actions of cocaine. SynCAM-dependent pathways may therefore represent novel points of therapeutic intervention after exposure to drugs of abuse.Neuropsychopharmacology advance online publication, 21 November 2012; doi:10.1038/npp.2012.226.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2012; 38(4). DOI:10.1038/npp.2012.226 · 7.05 Impact Factor
Show more