Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision‐Making in Parkinson's Disease

Rajan, Roopa; Krishnan, Syam; Sarma, Gangadhara; Sarma, Sankara P.; Kishore, Asha

doi:10.1002/mdc3.12631

Cited by 12 publications

(8 citation statements)

References 22 publications

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“…Importantly, our goal was to assess whether variation in genetically mediated DA function predicted flexibility in decision‐making and not to identify SNPs that were predictive of PD incidence or disease severity. In that regard, our sample size is comparable to similar studies examining the contributions of genetic variation to aspects of decision‐making in healthy individuals and in PD (Frank et al, 2007; Frank & Hutchison, 2009; Nikolova et al, 2011; Rajan et al, 2018; Rodriguez‐Jimenez et al, 2006; Williams‐Gray et al, 2008). Second, we conducted a multi‐centre, within‐subject study, and the consistency of our main results across study sites enhances the generalizability of our findings.…”

Section: Discussionsupporting

confidence: 68%

Genetic variation in the dopamine system is associated with mixed‐strategy decision‐making in patients with Parkinson's disease

Parr

Riek

Coe

et al. 2022

Eur J of Neuroscience

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Decision‐making during mixed‐strategy games requires flexibly adapting choice strategies in response to others' actions and dynamically tracking outcomes. Such decisions involve diverse cognitive processes, including reinforcement learning, which are affected by disruptions to the striatal dopamine system. We therefore investigated how genetic variation in dopamine function affected mixed‐strategy decision‐making in Parkinson's disease (PD), which involves striatal dopamine pathology. Sixty‐six PD patients (ages 49–85, Hoehn and Yahr Stages 1–3) and 22 healthy controls (ages 54–75) competed in a mixed‐strategy game where successful performance depended on minimizing choice biases (i.e., flexibly adapting choices trial by trial). Participants also completed a fixed‐strategy task that was matched for sensory input, motor outputs and overall reward rate. Factor analyses were used to disentangle cognitive from motor aspects within both tasks. Using a within‐subject, multi‐centre design, patients were examined on and off dopaminergic therapy, and genetic variation was examined via a multilocus genetic profile score representing the additive effects of three single nucleotide polymorphisms (SNPs) that influence dopamine transmission: rs4680 (COMT Val158Met), rs6277 (C957T) and rs907094 (encoding DARPP‐32). PD and control participants displayed comparable mixed‐strategy choice behaviour (overall); however, PD patients with genetic profile scores indicating higher dopamine transmission showed improved performance relative to those with low scores. Exploratory follow‐up tests across individual SNPs revealed better performance in individuals with the C957T polymorphism, reflecting higher striatal D2/D3 receptor density. Importantly, genetic variation modulated cognitive aspects of performance, above and beyond motor function, suggesting that genetic variation in dopamine signalling may underlie individual differences in cognitive function in PD.

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Section: Discussionsupporting

confidence: 68%

Genetic variation in the dopamine system is associated with mixed‐strategy decision‐making in patients with Parkinson's disease

Parr

Riek

Coe

et al. 2022

Eur J of Neuroscience

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“…On the other hand, previous studies showed that the CT genotype in one of the most studied variants associated with ICDs in PD, the Ser9‐to‐Gly substitution at DRD3 (rs6280), was a predictor of ICDs, and it induced a plausible biological effect [33,34]. Also, in a Spanish population, the presence of the C allele induced a higher risk of ICDs in their early‐onset subgroup, but this association was not replicated in the whole cohort [35].…”

Section: Discussionmentioning

confidence: 99%

Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease

Jesús

Periñán

Cortes

et al. 2020

Euro J of Neurology

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Background and purposeImpulse control disorders (ICDs) are frequent in Parkinson’s disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD.MethodsWe included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease for ICDs screening. Motor, nonmotor, and treatment‐related features were evaluated according to the presence of ICDs. Twenty‐one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs.ResultsImpulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical–genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms.ConclusionsPolymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient’s genetic background to identify individuals at risk for ICDs.

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“…Recently, some studies reported that DRD3 Ser9Gly polymorphism was associated with impulse-control disorders in PD patients, but their results were inconsistent [4–6]. Rajan et al found that DRD3 Ser9Gly polymorphism is associated with aberrant decision-making under uncertainty in PD patients without active impulse-control disorders [7]. Goetz et al observed that there was a higher frequency of the Gly allele in the hallucinators [8], while Wang et al reported that no significant difference was found between hallucinators and nonhallucinators in the DRD3 Ser9Gly genotypic or allelic distributions [2].…”

Section: Discussionmentioning

confidence: 99%

The Association between DRD3 Ser9Gly Polymorphism and Depression Severity in Parkinson’s Disease

Zhi

Yuan

et al. 2019

Parkinson's Disease

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More and more evidence suggests that dopamine receptor D3 gene (DRD3) plays an important role in the clinical manifestations and the treatment of Parkinson’s disease (PD). DRD3 Ser9Gly polymorphism is the most frequently studied variant point. Our aim was to investigate the potential effect of DRD3 Ser9Gly polymorphism on modulating resting-state brain function and associative clinical manifestations in PD patients. We consecutively recruited 61 idiopathic PD patients and 47 healthy controls (HC) who were evaluated by clinical scales, genotyped for variant Ser9Gly in DRD3, and underwent resting-state functional magnetic resonance imaging. Based on DRD3 Ser9Gly polymorphism, PD patients and HCs were divided into four subgroups. Then, two-way analysis of covariance (ANCOVA) was applied to investigate main effects and interactions of PD and DRD3 Ser9Gly polymorphism on the brain function via amplitude of low-frequency fluctuations (ALFF) approach. The association between DRD3 Ser9Gly-modulated significantly different brain regions, and clinical manifestations were detected by Spearman’s correlations. PD patients exhibited decreased ALFF values in the right inferior occipital gyrus, lingual gyrus, and fusiform gyrus. A significant difference in the interaction of “groups × genotypes” was observed in the right medial frontal gyrus. The ALFF value of the cluster showing significant interactions was positively correlated with HAMD-17 scores (r=0.489, p=0.011) and anhedonia scores (r=0.512, p=0.008) in PD patients with the Ser/Gly or Gly/Gly genotypes. Therefore, D3 gene Ser9Gly polymorphism might be associated with the severity of depression characterized by anhedonia in PD patients.

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Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision‐Making in Parkinson's Disease

Cited by 12 publications

References 22 publications

Genetic variation in the dopamine system is associated with mixed‐strategy decision‐making in patients with Parkinson's disease

Genetic variation in the dopamine system is associated with mixed‐strategy decision‐making in patients with Parkinson's disease

Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease

The Association between DRD3 Ser9Gly Polymorphism and Depression Severity in Parkinson’s Disease

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