Cross‐Cohort Evidence Links KCNJ6 rs702859 to Impulsive–Compulsive Phenotypes in Parkinson's Disease

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.