Munafò MR, Matheson IJ, Flint J. Association of the DRD2 gene Taq1A polymorphism and alcoholism: a meta-analysis of case-control studies and evidence of publication bias. Mol Psychiatry 12: 454-461

Department of Experimental Psychology, University of Bristol, Bristol, UK.
Molecular Psychiatry (Impact Factor: 14.5). 05/2007; 12(5):454-61. DOI: 10.1038/
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We investigated the association of the dopamine D2 receptor (DRD2) Taq1A polymorphism and alcoholism, using meta-analytic techniques, and specifically undertook an investigation of possible publication bias. Potential publication bias represents a genuine risk to the integrity of published research, but its impact has rarely been documented. We observed a small effect of the DRD2 Taq1A polymorphism on risk of alcoholism, indicating increased alcoholism in individuals possessing the A1 allele of the Taq1A polymorphism (OR=1.21, 95% CI 1.13-1.30, P<0.001). This association remained significant when data from samples of European and East Asian ancestry were analyzed separately. We did not find evidence for association in high-severity alcoholism compared to low-severity alcoholism. Removing the first published study significantly reduced the magnitude of the pooled effect size estimate, although the association remained significant. In addition, we observed evidence for possible publication bias and for the strength of individual study effect size to be inversely related to year of publication. These results support the association of the DRD2 Taq1A polymorphism with alcoholism. This conclusion is qualified by the possibility of publication bias in the literature and the observed between-study heterogeneity, which indicates that the observed association may differ in strength between populations or may not exist at all in some populations.

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    • "genotype (hetero-or homozygous for A1) (Blum et al. 1990). Two meta-analyses of Caucasian alcoholics and controls nonetheless support a link between the A1 allele and alcoholism (Munafo et al. 2007; Smith et al. 2008). Currently, the A1 allele is recognized as a risk factor for alcoholism (Agrawal et al. 2012). "
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    ABSTRACT: The ankyrin repeat and kinase domain containing 1 (ANKK1) TaqIA polymorphism has been extensively studied as a marker of the gene for dopamine receptor D2 (DRD2) in addictions and other dopamine-associated traits. In vitro mRNA and protein studies have shown a potential connection between ANKK1 and the dopaminergic system functioning. Here, we have investigated whether Ankk1 expression in the brain is regulated by treatment with dopaminergic agonists. We used quantitative RT-PCR of total brain and Western blots of specific brain areas to study Ankk1 in murine brain after dopaminergic treatments. We found that Ankk1 mRNA was upregulated after activation of D1R-like dopamine receptors with SKF38393 (2.660 ± 1.035-fold; t: 4.066, df: 11, P = 0.002) and apomorphine (2.043 ± 0.595-fold; t: 3.782, df: 8, P = 0.005). The D2R-like agonist quinelorane has no effect upon Ankk1 mRNA (1.004 ± 0.580-fold; t: 0.015, df: 10, P = 0.9885). In contrast, mice treatment with the D2R-like agonists 7-OH-DPAT and aripiprazole caused a significant Ankk1 mRNA downregulation (0.606 ± 0.057-fold; t: 2.786, df: 10, P = 0.02 and 0.588 ± 0.130-fold; t: 2.394, df: 11, P = 0.036, respectively). With respect the Ankk1 proteins profile, no effects were found after SKF38393 (t: 0.54, df: 2, P = 0.643) and Quinelorane (t: 0.286, df: 8, P = 0.782) treatments. In contrast, the D2R-like agonist 7-OH-DPAT (±) caused a significant increment of Ankk1 in the striatum (t: 2.718, df: 7; P = 0.03) when compared to the prefrontal cortex. The activation of D1R-like and D2-R-like leads to opposite transcriptional regulation of Ankk1 by specific pathways.
    Neurotoxicity Research 07/2015; DOI:10.1007/s12640-015-9545-9 · 3.54 Impact Factor
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    • "Among these, the Taq1A polymorphism (rs1800497) of the DRD2 gene is a substitution located in a noncoding region of the DRD2 locus. The A1 allele (as opposed to the A2 allele) of this polymorphism was shown to be robustly associated with alcohol dependence through a meta-analysis (Munafo et al., 2007). A previous metaanalysis of the association between this DRD2 polymorphism and substance dependence (Munafò et al., 2009). "
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    ABSTRACT: Previous neuroscientific studies have shown that the dopaminergic system plays an important role in creative potential measured by divergent thinking (CPMDT), emotional control, and motivational state. However, although associations between two of these four components have been previously established (e.g., the association between CPMDT and emotional control, the association between CPMDT and motivational state, etc.), the interactions between these four remain unknown. The purpose of this study was to reveal these interactions using path analyses. The Taq1A polymorphism of the dopamine D2 receptor (DRD2) gene was used for this purpose. For measuring emotional intelligence (EI), we used the Japanese version of the Emotional Intelligence Scale. CPMDT was measured using the S-A creativity test. Motivational state was measured using the Vigor subscale of the Japanese version of the Profile of Mood Scale (POMS). Data from 766 healthy, right-handed individuals (426 men and 340 women; 20.7 ± 1.9 years of age) were used in this study. There were significant and robust positive relationships among measures of CPMDT, EI, and motivational state across sex. In addition, the polymorphism of the DRD2 gene was significantly associated with EI, specifically in females. Path analysis in females indicates that the model in which (a) the DRD2 polymorphism primarily facilitates EI, (b) EI in turn facilitates CPMDT and leads to a better motivational state, and (c) a better motivational state also directly facilitates CPMDT explains the data in the most accurate manner. This study suggested a comprehensive picture of the cascade of the associations among dopamine, EI, motivational state, and CPMDT at least in females.
    Frontiers in Psychology 07/2015; 6:912. DOI:10.3389/fpsyg.2015.00912 · 2.80 Impact Factor
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    • "Since that time there have been no less than 3738 (Pubmed-6-23-14) peer reviewed articles on many peripheral and central nervous system (CNS) behaviors and physiological processes. Understandably addiction or even the broader term RDS involves very complex gene × environment interaction and one cannot expect that a single gene like the DRD2 gene would have a powerful effect by itself, however, albeit many negative findings, there is still a plethora of evidence for the role of the DRD2 gene polymorphisms and a number (small sample of studies represented herein) of addictive and other reward dependent behaviors including: alcohol dependence (Pato et al., 1993; Ponce et al., 2003; Munafò et al., 2007; Smith et al., 2008; Pinto et al., 2009; Grzywacz et al., 2012; Wang et al., 2013); drug dependence (Li et al., 2004; Xu et al., 2004; Young et al., 2004; Barratt et al., 2006; Li et al., 2006; Hou and Li, 2009; Chen et al., 2011a,b; Al-Eitan et al., 2012; Jacobs et al., 2013; Lee et al., 2013; Ohmoto et al., 2013; Sullivan et al., 2013; Suraj Singh et al., 2013; Vereczkei et al., 2013; Wang et al., 2013; Clarke et al., 2014; Roussotte et al., 2014; Schuck et al., 2014); mood disorders (Vaske et al., 2009; Huertas et al., 2010; Zhu et al., 2011; Zou et al., 2012; Hettinger et al., 2012; Jutras-Aswad et al., 2012; Tsuchimine et al., 2012; Whitmer and Gotlib, 2012; Zai et al., 2012; Peciña et al., 2013; Zhang et al., 2014); rearing behaviors (Mills-Koonce et al., 2007; Bakermans-Kranenburg and van Ijzendoorn, 2011; Beaver and Belsky, 2012; Masarik et al., 2014); obesity (Spangler et al., 2004; Fang et al., 2005; Huang et al., 2005; Epstein et al., 2007; Nisoli et al., 2007; Barnard et al., 2008; Blum et al., 2008; Eny et al., 2009; Epstein et al., 2010; Mathes et al., 2010; Stice et al., 2010; van Strien et al., 2010; Jabłoński, 2011; Anitha et al., 2012; Chen et al., 2012; Winkler et al., 2012; Ariza et al., 2013; Carpenter et al., 2013; Cameron et al., 2013; Hess et al., 2013; Alsiö et al., 2014); Anorexia Nervosa (Bergen et al., 2005); motivation (Trifilieff et al., 2013); brain metabolism (Noble et al., 1997); ADHD (Gold et al., 2014), and pathological gambling (Gyollai et al., 2014). "
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    ABSTRACT: Obesity and many well described eating disorders are accurately considered a global epidemic. The consequences of Reward Deficiency Syndrome, a genetic and epigenetic phenomena that involves the interactions of powerful neurotransmitters, are impairments of brain reward circuitry, hypodopaminergic function and abnormal craving behavior. Numerous sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Important facts which could translate to potential therapeutic targets espoused in this review include: 1) brain dopamine (DA) production and use is stimulated by consumption of alcohol in large quantities or carbohydrates bingeing; 2) in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; 3) highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; 4) blood glucose and cerebrospinal fluid concentrations of homovanillic acid, the dopamine metabolite, are significantly correlated and 5) 2-deoxyglucose the glucose analogue, in pharmacological doses associates with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and human fMRI support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and DA-modulated reward circuits are involved in pathologic eating behaviors. Treatment for addiction to glucose and drugs alike, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy, in contrast to current theories and practices that use dopamine antagonists. Until now, powerful dopamine-D2 agonists have failed clinically, due to chronic down regulation of D2 receptors instead, consideration of novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of reward deficiency.
    Frontiers in Psychology 09/2014; 5:919. DOI:10.3389/fpsyg.2014.00919 · 2.80 Impact Factor
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