Objective: To investigate the association between polymorphisms related to reward and punishment processing, and the development of impulse control disorders (ICDs) and compulsive behaviors (CBs) in patients with Parkinson’s disease (PD).

Background: Impulse control and related disorders (ICBDs) are frequent and disabling non-motor complications in PD, most commonly associated with dopamine replacement therapy (DRT) [1][2]. However, only a subset of patients exposed to DRT develop ICBDs, indicating a substantial but largely unexplained genetic contribution.

Method: Two independent cohorts were analysed: a cross-sectional local cohort (n=449) and a longitudinal cohort from the Parkinson’s Progression Markers Initiative (PPMI; n=433) [3]. ICDs and CBs were assessed using the full version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) in the local cohort and the short form in PPMI [4]. Dopaminergic therapy was quantified as levodopa equivalent dose [5]. Case-control analyses of single nucleotide polymorphisms (SNPs) in candidate genes identified by systematic review were performed. Significant associations were further examined using random-effects meta-analysis and interaction analyses with dopaminergic therapy. In silico functional annotation was conducted for relevant variants.

Results: The KCNJ6 synonymous variant rs702859 was associated with increased risk of CBs in the local cohort (OR=1.46, 95% CI 1.02–2.09) and ICDs in the PPMI cohort (OR=1.60, 95% CI 1.14–2.25). Homozygous carriers exhibited higher ICD risk at lower dopamine agonist doses. Meta-analysis confirmed a significant association (pooled OR=1.38, 95% CI 1.01–1.87). Functional annotation indicated linkage disequilibrium between rs702859 and rs146589674, a variant potentially affecting gene expression.

Conclusion: KCNJ6:rs702859 is associated with susceptibility to ICDs in PD, supporting a role for GIRK2 channel dysfunction. These findings suggest KCNJ6 as a therapeutic target and highlight the importance of personalized dopaminergic therapy in PD.

Previous Presentation: This work was previously presented at the 77th Annual Meeting of the Spanish Society of Neurology (SEN), November 19, 2025.

References: [1] Debove I, Paschen S, Amstutz D, et al. Management of Impulse Control and Related Disorders in Parkinson’s Disease: An Expert Consensus. Mov Disord 2024;39(2):235-48. doi: 10.1002/mds.29700 [published Online First: 2024/01/18]
[2] Weintraub D, David AS, Evans AH, et al. Clinical spectrum of impulse control disorders in Parkinson’s disease. Mov Disord 2015;30(2):121-7. doi: 10.1002/mds.26016 [published Online First: 20141105]
[3] Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol 2011;95(4):629-35.
[4] Weintraub D, Hoops S, Shea JA, et al. Validation of the questionnaire for impulsive‐compulsive disorders in Parkinson’s disease. Mov Disord 2009;24(10):1461-67
[5] Jost ST, Kaldenbach MA, Antonini A, et al. Levodopa Dose Equivalency in Parkinson’s Disease: Updated Systematic Review and Proposals. Mov Disord 2023;38(7):1236-52. doi: 10.1002/mds.29410 [published Online First: 2023/05/06]

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-variation-in-kcnj6-gene-increases-risk-of-impulse-disorders-in-parkinsons-disease-a-two-cohort-study/