Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson’s disease patients

Krishnamoorthy, S.; Rajan, Roopa; Banerjee, Moinak; Kumar, Harish; Sarma, Gangadhara; Krishnan, Syam; Sarma, Sankara P.; Kishore, Asha

doi:10.1016/j.parkreldis.2016.06.005

Cited by 50 publications

(43 citation statements)

References 25 publications

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“…Early genetic association studies in the general population have suggested that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling . In PD, ICDs and related behaviors have been associated with genes encoding dopamine receptors ( DRD1, DRD2, DRD3 ), serotonin ( HTR2A ), and glutamate ( GRIN2B ) receptors, as well as the dopamine transporter ( DAT1 ) and the serotonin metabolism enzyme tryptophan hydroxylase ( TPH2 ) . Gene‐gene interactions between different neurotransmitter systems are probably important, as recently suggested for genes within the serotonin and dopamine systems, although these analyses require larger sample sizes to be sufficiently powered.…”

Section: Discussionmentioning

confidence: 55%

“…Genetic association studies in the general population suggested multigene heritability involving multiple neurotransmitter systems including dopamine, norepinephrine, serotonin, glutamate, and opioid systems . In PD, a few genetic association studies have confirmed some of these associations, although others did not, suggesting overlapping but distinct mechanisms . However, most association studies in PD suffered from limited sample size and lack of control for multiple comparisons, and their results have not been replicated in independent cohorts.…”

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confidence: 99%

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Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease

et al. 2018

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Background Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. Methods We performed a multicenter case‐control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa‐equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. Results The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32‐0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40‐base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24‐2.68; P = 0.0021; Bonferroni adjusted P = 0.105). Conclusions Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease

et al. 2018

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“…Furthermore, the same genotype was also associated with higher response rate in treatment with pramipexole [23]. Another study showed that heterozygous genotype carriers of this were more prone to develop ICDs [38]. Lastly, Gly/Gly genotype of rs6280 was associated with higher doses of DA needed to manage PD [39].…”

Section: Genetic Factors and Treatment Response In Pdmentioning

confidence: 94%

“…Moreover, DRD2 rs1799732 Ins/Ins genotype was associated with gastrointestinal AEs (nausea and vomiting) after L-Dopa therapy [36]. Association of DRD3 variants with drug outcome in PD was shown in at least five pharmacogenetic studies [23,[36][37][38][39]. DRD3 rs6280 AA genotype (Ser/Ser) was shown to be associated with increased risk for developing ICDs and gastrointestinal AE [36,37].…”

Section: Genetic Factors and Treatment Response In Pdmentioning

confidence: 99%

Effects of Genetic Variability in Dopaminergic Pathway on Treatment Response in Parkinson’s Disease

Redenšek¹,

Trošt²,

Dolžan³

2018

Parkinson's Disease - Understanding Pathophysiology and Developing Therapeutic Strategies

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Parkinson's disease (PD) is a chronic progressive neurodegenerative brain disorder presenting with motor signs and symptoms, such as akinesia, rest tremor, rigidity, and later in disease progression postural instability. However, nonmotor symptoms may harm patients' quality of life even more than the motor ones. The etiopathogenesis is not clear yet. PD may develop due to a combination of genetic and environmental factors. It is treated symptomatically with dopaminergic drugs. The gold standard of PD management is L-Dopa, however also other drugs are frequently used, such as dopamine agonists, MAOB inhibitors, COMT inhibitors, and occasionally amantadine and anticholinergic drugs. Many patients experience several adverse events of L-Dopa treatment, such as different motor complications. Furthermore, nonmotor adverse events of dopaminergic treatment may occur. The efficacy of drugs varies between patients as well. Several polymorphic genes have already been associated with treatment outcome in PD, such as metabolic enzymes, transport and receptor genes, and might serve as treatment outcome prediction factors. As gene-environment interactions were also shown to contribute to PD development, they might also be able to predict treatment response. Such genetic biomarkers could be helpful in personalized care of PD patients to prevent adverse events and inefficacy of a certain drug.

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“…Although many neurotransmitter systems besides dopamine are affected in PD, little is known about their contribution to ICDs. Regarding genetics, there is evidence, although mixed, from cross‐sectional studies that TaqIA ANKK1 and DRD3 p.Ser9Gly single nucleotide polymorphisms (SNPs) are associated with ICDs in PD, and for contribution of COMT Val158Met to motor impulsivity as a possible risk factor for behavioral impulsivity …”

Section: Neural Substrate: Compelling and Complicatedmentioning

confidence: 99%

Impulse control disorders in Parkinson's disease: A 20‐year odyssey

Weintraub

2019

Movement Disorders

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Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson’s disease patients

Cited by 50 publications

References 25 publications

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease

Effects of Genetic Variability in Dopaminergic Pathway on Treatment Response in Parkinson’s Disease

Impulse control disorders in Parkinson's disease: A 20‐year odyssey

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