Movement disorders : official journal of the Movement Disorder Society · 2026
Cross-Cohort Evidence Links KCNJ6 rs702859 to Impulsive-Compulsive Phenotypes in Parkinson's Disease.
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García-Díaz Sergio, Martín-Rodríguez Juan Francisco, Muñoz-Delgado Laura, Díaz-Belloso Rafael, Jesús Silvia, Periñán María Teresa, Martín-Bórnez Miguel, Castellano-Guerrero Ana M, Ojeda-Lepe Elena, Macías-García Daniel, Adarmes-Gómez Astrid, Buiza-Rueda Dolores, Bonilla-Toribio Marta, Iglesias-Camacho Elena, San-Eufrasio Manuela, Pérez-Calvo Cristina, Pineda-Sánchez Rocío, Gómez-Campos Francisco Javier, Luque-Ambrosiani Antonio, Carrillo-García Fátima, Gómez-Garre Pilar, Mir Pablo
Аннотация
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.
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.