Cross-Cohort Evidence Links KCNJ6 rs702859 to Impulsive-Compulsive Phenotypes in Parkinson's Disease
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Updated: Oct 24, 2026

Gait Analysis of Age-dependent Motor Impairments in Mice with Neurodegeneration
Published on: June 18, 2018
Sergio García-Díaz1,2,3, Juan Francisco Martín-Rodríguez1,2,4, Laura Muñoz-Delgado1,2
1Unidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen Del Rocío/Universidad de Sevilla, Sevilla, Spain.
Background:
Impulse control disorders (ICDs) and related compulsive behaviors (CBs) are frequent non-motor complications of Parkinson's disease (PD) with a probable genetic contribution.
Objective:
To investigate whether genetic variants involved in reward and punishment processing are associated with impulsive-compulsive phenotypes in PD.
Methods:
We analyzed a cross-sectional Seville cohort (N = 449) and an independent Parkinson's Progression Markers Initiative (PPMI) cohort (N = 433) with longitudinally collected assessments. ICDs and CBs were assessed with the full QUIP (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease) in Seville and the short form (QUIP-S) in PPMI. Dopaminergic exposure was quantified as levodopa- and dopamine agonist-equivalent daily doses. A candidate-variant panel selected through systematic review was evaluated using covariate-adjusted case-control analyses with empirical P-values from 5000 permutations, followed by random-effects meta-analysis, exploratory genotype-by-treatment analyses, and in silico functional annotation.
Results:
rs702859, a synonymous KCNJ6 variant, was associated with CBs in Seville (odds ratio [OR] 1.46; 95% confidence interval [CI] 1.02-2.09) and with ICDs in PPMI (OR 1.56; 95% CI 1.11-2.19). Meta-analysis supported an association with ICDs (pooled OR 1.36; 95% CI 1.03-1.80). Exploratory analyses showed nominal interactions between rs702859 and dopamine agonist dose in Seville that were not reproduced in PPMI. rs702859 was in strong linkage disequilibrium with rs146589674, a KCNJ6 3' untranslated region variant; expression, chromatin accessibility, and methylation quantitative trait loci (QTL) data linked risk alleles to reduced KCNJ6 expression.
Conclusions:
KCNJ6 rs702859 showed convergent variant-level associations across related impulsive-compulsive phenotypes in two independent cohorts, supporting further investigation of KCNJ6-related pathways. Independent functional and clinical validation is required. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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