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      The genetics of addiction—a translational perspective

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          Abstract

          Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.

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          Most cited references171

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          Attentional bias in addictive behaviors: a review of its development, causes, and consequences.

          A wealth of research from the past two decades shows that addictive behaviors are characterized by attentional biases for substance-related stimuli. We review the relevant evidence and present an integration of existing theoretical models to explain the development, causes, and consequences of addiction-related attentional biases. We suggest that through classical conditioning, substance-related stimuli elicit the expectancy of substance availability, and this expectancy causes both attentional bias for substance-related stimuli and subjective craving. Furthermore, attentional bias and craving have a mutual excitatory relationship such that increases in one lead to increases in the other, a process that is likely to result in substance self-administration. Cognitive avoidance strategies, impulsivity, and impaired inhibitory control appear to influence the strength of attentional biases and subjective craving. However, some measures of attentional bias, particularly the addiction Stroop, might reflect multiple underlying processes, so results need to be interpreted cautiously. We make several predictions that require testing in future research, and we discuss implications for the treatment of addictive behaviors.
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            A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

            Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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              The PhenX Toolkit: Get the Most From Your Measures

              The potential for genome-wide association studies to relate phenotypes to specific genetic variation is greatly increased when data can be combined or compared across multiple studies. To facilitate replication and validation across studies, RTI International (Research Triangle Park, North Carolina) and the National Human Genome Research Institute (Bethesda, Maryland) are collaborating on the consensus measures for Phenotypes and eXposures (PhenX) project. The goal of PhenX is to identify 15 high-priority, well-established, and broadly applicable measures for each of 21 research domains. PhenX measures are selected by working groups of domain experts using a consensus process that includes input from the scientific community. The selected measures are then made freely available to the scientific community via the PhenX Toolkit. Thus, the PhenX Toolkit provides the research community with a core set of high-quality, well-established, low-burden measures intended for use in large-scale genomic studies. PhenX measures will have the most impact when included at the experimental design stage. The PhenX Toolkit also includes links to standards and resources in an effort to facilitate data harmonization to legacy data. Broad acceptance and use of PhenX measures will promote cross-study comparisons to increase statistical power for identifying and replicating variants associated with complex diseases and with gene-gene and gene-environment interactions.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                July 2012
                17 July 2012
                1 July 2012
                : 2
                : 7
                : e140
                Affiliations
                [1 ]simpleDepartment of Psychiatry, Washington University School of Medicine , Saint Louis, MO, USA
                [2 ]simpleGenetic Epidemiology, Queensland Institute of Medical Research , Brisbane, QLD, Australia
                [3 ]simpleSchool of Psychology, University of Queensland , Brisbane, QLD, Australia
                [4 ]simpleVirginia Institute of Psychiatric and Behavioral Genetics, VCU , Richmond, VA, USA
                [5 ]simpleDepartment of Psychological Sciences, University of Missouri , Columbia, MO, USA
                Author notes
                [* ]simpleDepartment of Psychiatry, Washington University School of Medicine , 660 S. Euclid, CB 8234, Saint Louis, MO 63110, USA. E-mail: arpana@ 123456wustl.edu
                Article
                tp201254
                10.1038/tp.2012.54
                3410620
                22806211
                955a8262-638c-4a8d-afed-d3bc7acd80fa
                Copyright © 2012 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 30 May 2012
                : 30 May 2012
                Categories
                Review

                Clinical Psychology & Psychiatry
                addiction,substance,drug,genetics
                Clinical Psychology & Psychiatry
                addiction, substance, drug, genetics

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