Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson's disease

Abstract

We aimed to assess whether allelic variants of dopamine receptor, glutamate receptor, and serotonin transporter genes are associated with the appearance of impulse control and related behaviors (ICRB) in Parkinson's disease (PD) with dopamine replacement therapy (DRT). We surveyed ICRB in consecutive Korean patients with PD who were treated with stable DRT using modified Minnesota Impulsive Disorders Interview over a period of 4 months. In the 404 patients who completed the interview and the 559 Korean healthy normal controls, genotyping was performed for variants of the DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.366C>G, c.2664C>T and c.-200T>G, and the promoter region of the serotonin transporter gene (5-HTTLPR). Behavioral abnormalities suggestive of ICRB including compulsive buying, gambling, sexual behavior and eating, and punding, were present in 14.4% of the patients. Variants of DRD2 and 5-HTTLPR were not associated with the risk of developing ICRB. However, the AA genotype of DRD3 p.S9G and the CC genotype of GRIN2B c.366C>G were more frequent in patients with ICRB than in nonaffected patients (odds ratio [OR] = 2.21, P = 0.0094; and 2.14, P = 0.0087, after adjusting for age and sex). After controlling for clinical variables in the multivariate analysis, carriage of either AA genotype of DRD3 or CC genotype of GRIN2B was identified as an independent risk factor for ICRB (adjusted OR: 2.57, P = 0.0087). Variants of DRD3 p.S9G and GRIN2B c.366C>G may be associated with the appearance of ICRB in PD.

The factors associated with impulse control behaviors in Parkinson's disease: A 2‐year longitudinal retrospective cohort study

“…Medication practices, cost burdens, and health insurance have been suggested as potential factors with influencing the different prevalences (Fan et al., 2009). Genetic variants of serotonin receptors and polymorphisms for the dopaminergic, serotonergic, glutamate, and opioidergic systems have been related to the development of ICB in patients with PD (Comings & Blum, 2000; Ibanez, Blanco, Perez de Castro, Fernandez‐Piqueras, & Saiz‐Ruiz, 2003; Kraemmer et al., 2016; Le Foll, Gallo, Le Strat, Lu, & Gorwood, 2009; Lee, Jeon, Kim, & Park, 2012; Lee et al., 2009; Zainal Abidin et al., 2015). Thus, genetic variations in receptors, transporters, or enzymes of the catecholaminergic, serotonergic, glutamatergic, and opioid neurotransmission systems are potentially associated with ICD in PD (Jimenez‐Urbieta et al., 2015).…”

The Pathophysiology of Impulse control Disorders in Parkinson Disease

“…Dopamine D3 receptors, predominantly distributed within the limbic system [6,16] regulate dopamine release within the mesocorticolimbic pathway [17]. The association of the DRD3 p.S9G polymorphism in the development of ICDs in PD may be explained by this form of the receptor demonstrating a reduced binding affinity to dopamine [35], which may result in inappropriate dopamine-mediated stimulation of the mesocorticolimbic pathway.…”

“…No such association has been found for other variants of dopamine receptors [35]. Eisenegger et al [36] has also demonstrated a further possible genetic component that may influence the development of compulsive behaviours in patients with PD: administration of L-DOPA was found to result in significantly greater gambling tendencies in healthy males with the dopamine receptor 4/7 polymorphism genotype compared to the 4/4 polymorphism.…”

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

“…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].…”