Objective: To identify the genetic factors associated with Impulse control disorders (ICDs) in Parkinson’s disease (PD) patients using a genome-wide approach.

Background: ICDs are associated with dopamine replacement therapy (DRT), especially dopamine agonists (DA), in PD patients. A few genetic polymorphisms have been shown to modulate the susceptibility to ICDs in candidate studies. However, unbiased genetic association studies are lacking, and the genetic basis of ICDs in PD remains largely unknown.

Method: We collected phenotypic and genetic data from five international cohorts of sporadic PD patients (BADGE-PD, DIG-PD, ICEBERG, PARKWEST, PPMI). Cases (PD+ICD+) were PD patients developing ICD during follow-up, being defined by different scales standardized and transformed into binary outcome (presence/absence of ICDs). Controls were PD patients without ICD during follow-up. Illumina NeuroX, Neurochip or Megachip mircoarrays were used for DNA genotyping. Quality controls, data harmonization and imputation steps were performed on the same site with the same criteria to minimize heterogeneity bias. Genome-wide association analysis was performed on the merged dataset using generalized linear mixed models to take into account for potential cohort effect, population structures, gender, age at diagnosis and use of DRT. GWAS p-value for significance was set at 10-8.

Results: The analysis was performed on 1,255 PD patients: 513 PD+ICD+ with a mean (SD) age 61 (8.1) years, 33% female, disease duration 4.6 (3.2) years, 80% treated with DA; 742 PD+ICD-, age 69 (9.3) years, 41% female, disease duration 4.3 (2.9) years, 64% treated with DA. Using a minor allele frequency threshold >0.05 and INFO score >0.9 for imputation accuracy, we analyzed 5,034,118 SNPs. We found 5 independant GWAS-significant loci on chromosome 7 (p=1.91E-08), 6 (p=2.21E-08), 10 (p=9.76E-09), 11 (p=3.31E-09) and 15 (p=8.70E-09). Some of the significant SNPs were located near genes encoding proteins involved in glutamate and GABA neurotransmitter systems.

Conclusion: We report here the first of a genome-wide association study on ICDs in PD. Our preliminary results are suggestive for novel associations of genetic polymorphisms with ICDs in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gwas-on-impulse-control-disorders-in-parkinsons-disease/