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The TaqIA single-nucleotide polymorphism (SNP), which is the most widely studied genetic polymorphism in addictions, is located at the gene that encodes the RIP kinase ANKK1 near the gene for dopamine receptor D2. The TaqIA SNP is in strong linkage disequilibrium with the SNP rs7118900, which changes the alanine at position 239 to threonine in the ANKK1 protein (Ala239/A2; Thr239/A1). In silico analysis has predicted that this polymorphic substitution creates an additional phosphorylation site in the kinase domain of ANKK1. To investigate the contribution of ANKK1 to the pathophysiology of TaqIA-associated phenotypes, we analyzed transfected HEK293T cells with the human ANKK1-kinase and ANKK1-kinase variants tagged with GFP. We observed that the ANKK1-kinase is located in both the nucleus and the cytoplasm, suggesting that there is nucleocytoplasmic shuttling of this putative signal transducer. In addition, we found that the Ala239Thr ANKK1-kinase polymorphism exhibited strong expression differences in both the nucleus and the cytoplasm at basal level and when stimulated with the dopamine agonist apomorphine. Specifically, the ANKK1-kinase variant showed the highest level of basal protein expression, while ANKK1-kinase was 0.64-fold lower. After treatment with apomorphine, ANKK1-kinase showed a 2.4-fold increment in protein levels, whereas a 0.67-fold reduction was observed in ANKK1-kinase. Thus, here we provide the first evidence of functional ANKK1 differences that are marked by TaqIA and could be associated with vulnerability to addiction. [ABSTRACT FROM AUTHOR]

Polymorphisms of DRD2 and A NKK1 have been associated with psychiatric syndromes where there is believed to be an underlying learning process deficit such as addiction, post-traumatic stress disorder and psychopathy. We investigated the effects of the DRD2 C957T and ANKK1 TaqIA single nucleotide polymorphism (SNP), which have been associated with psychopathic traits in alcoholic patients, on fear conditioning and aversive priming in healthy volunteers. We found that the DRD2 C957T SNP, but not the ANKK1 TaqIA SNP, was associated with both differential conditioning of the skin conductance response and the aversive priming effect. There were no differences between the genotype groups with respect to the extinction of the skin-conductance conditioned response. These results suggest that the C957T SNP could be related to learning differences associated with the risk of developing psychiatric disorders in individuals that are carriers of the C homozygous genotype. Our genetic data raise the possibility that the dopaminergic system functional variations determined by this SNP could affect fear learning. [ABSTRACT FROM AUTHOR]

Objective: The objective was to confirm whether a homozygous genotype for the C957 allele of the C957T DRD2 gene single nucleotide polymorphism (SNP) is associated with schizophrenia in an independent study population. Method: We examined the genotypic distribution of this SNP in a set of clinically ascertained schizophrenic patients ( n = 131) and age-matched control subjects ( n = 364). Individuals were genotyped using automated analysis of fluorescently labeled PCR products. Results: The distribution of grouped genotypes for the C957T DRD2 SNP (CC vs. CT, TT) showed that C homozygote genotype was over-represented in our patient sample when compared with control subjects. This difference reaches the statistical significance ( χ2 = 7.0; df = 1; P = 0.008; OR = 2.05; % CI 1.2–3.4). Conclusion: The findings of this study provide additional evidence that genetic variation at the DRD2 gene plays an important role in the vulnerability to schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have associated a decreased striatal D2 dopamine receptor (DRD2) binding with impaired performance in cognitive tasks. In vivo studies have found a lower DRD2 binding associated with the CC genotype of the C957T single nucleotide polymorphism (SNP) of the DRD2 gene. Objective: The aim of this study was to investigate the relationship between executive functions and the C957T DRD2 SNP. We hypothesized that the CC genotype would be associated with a poorer executive functioning. Methods: Our sample consisted of 83 healthy volunteers (28 males and 55 females; mean age 25.2, SD 1.7 years). To assess executive functions, the Wisconsin Card Sorting Test was used, considering the variables perseverative errors, perseverative responses, and number of categories achieved. The genotype distribution was 13 CC, 41 CT, and29 TT, satisfying Hardy-Weinberg equilibrium. Results: Carriers of the CC genotype, compared with carriers of the CT/TT genotypes, achieved significantly fewer categories (5.00 vs. 5.81; p = 0.004), made a greater number of perseverative errors (13.46 vs. 8.39; p = 0.018), and had a greater number of perseverative responses (14.92 vs. 8.94; p = 0.014). Conclusions: Our results support the hypothesis that the C957T DRD2 SNP may influence cognitive performance through its repercussions on central dopaminergic function. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]