Single nucleotide polymorphisms in ANKK1 and the dopamine D2 receptor gene affect cognitive outcome shortly after traumatic brain injury: A replication and extension study

Department of Psychiatry, Section of Neuropsychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
Brain Injury (Impact Factor: 1.81). 09/2008; 22(9):705-14. DOI: 10.1080/02699050802263019
Source: PubMed


The two objectives of this study were (1) to replicate the previous finding that a single nucleotide polymorphism (SNP) in the ANKK1 gene (SNP rs1800497 formerly known as the DRD2 TAQ1 A allele) is associated with measures of learning and response latency after traumatic brain injury (TBI) and (2) to further characterize the genetic basis of the effect by testing the strength of association and degree of linkage disequilibrium between the cognitive outcome measures and a selected ensemble of 31 polymorphisms from three adjacent genes in the region of rs1800497.
A cohort of 54 patients with TBI and 21 comparison subjects were genotyped for the DRD2 TAQ1 A polymorphism (rs1800497). Ninety-three patients with TBI and 48 comparison subjects (the current cohort and an earlier independent cohort) were also genotyped for 31 additional neighbouring polymorphisms in NCAM, ANKK1 and DRD2. TBI patients were studied 1 month after injury. All subjects completed memory and attention tests, including the California Verbal Learning Test (CVLT) recognition task and the Gordon Continuous Performance Test (CPT).
As in a previous study the T allele of TAQ1 A (rs1800497) was associated with poorer performance on the CVLT recognition trial in both TBI and control subjects. There was also a significant diagnosis-by-allele interaction on CPT measures of response latency, largely driven by slower performance in the TBI participants with the T allele. Analysis of 31 additional neighbouring polymorphisms from NCAM, ANKK1 and DRD2 in the TBI patients showed four haploblocks. A haploblock of three SNPs in ANKK1 (rs11604671, rs4938016 and rs1800497 (TAQ1A)) showed the greatest association with cognitive outcome measures.
The results confirm a previously published association between the TAQ1 A (rs1800497) T allele and cognitive outcome measures 1 month after TBI and suggest that a haploblock of polymorphisms in ANKK1, rather than the adjacent DRD2 gene, has the highest association with these measures after TBI.

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Available from: Brenna C Mcdonald, Oct 04, 2015
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    • "The mutant type T-allele is also associated with appearance of spontaneous behavior and addiction to substances and alcohol (decision-making) (Esposito-Smythers et al., 2009). Perhaps these phenomena are also result of the close linkage of our gene with its neighboring DRD2 gene and of the possible interaction between them (McAllister et al., 2008). Specifically, Mc Alister et al. have shown that the T allele is associated with reduced expression of dopaminergic binding sites in the striatum of the brain. "
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    ABSTRACT: It is well known that intelligence consists of a variety of interactional and cognitive skills and abilities (e.g. tradecraft; critical and divergent thinking; perception of foreign information). Decision making is defined as the conscious choice between given options, relating to a problem. Both genetic background and environment comprise key elements for personality characteristics of the human being. The aim of this study is to determine the frequency distribution of rs324420, rs1800497, rs363050, rs6265, rs1328674 polymorphisms known to be involved in individual personality characteristics, in 830 Greek Subjects. The study is independent from direct clinical measurements (e.g. IQ measurements; physiological tests). The population of the volunteers is described, based on genotype, sex, with the respective gene frequencies, including the Minor Allele Frequency (MAF). A potential influence of the volunteer gender with the above characteristics (based on genotypes and alleles) is examined and finally, volunteers are classified as follows: A volunteer receives + 1, for each genotype/allele, which enhances his intelligence or his decision-making. In contrast, he receives − 1, for each genotype/allele, which relegates the individual characteristic. No statistically significant gender-characteristics correlation is observed. According to their genetic profile, a rate of 92.5%, of the volunteers may be characterized by prudence and temperance of thought, with only a small proportion of them (7.5%) may be classified as genetically spontaneous and adventurous. Regarding intelligence, the study population may lay around average and a little above it, at a rate of 96.3%, while the edges of the scale suggest only a 0.5% of the volunteers, who, although the “smartest”, somehow seem to lack prudence. In conclusion, individuals with low cognitive ability may be more prudent than others and vice versa, while the “smartest” ones tend to be more risky, in decision-making. Therefore, intelligence and decision-making may, after all, be less linked to each other than expected.
    Meta Gene 12/2014; Volume 2:844-853. DOI:10.1016/j.mgene.2014.10.006
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    • "Dopamine is a neurotransmitter that has a key role in numerous brain processes including movement, reward, learning, and plasticity [1]. Polymorphisms in the genes encoding for dopamine receptors and degradation enzymes contribute to inter-individual differences in some forms of learning [2], with polymorphisms that reduce dopamine neurotransmission thought to impair learning and cognitive performance, and those that increase dopamine neurotransmission improving these behaviors [3], [4]. These genetic influences on dopamine-related learning are thought to be paralleled by gene effects on brain plasticity [5]; for example, studies of cognitive flexibility and working memory show differences in prefrontal and striatal activation in relation to variation in dopamine genetics [6], [7], [8]. "
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    ABSTRACT: Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.
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