Clinical-genetic model predicts incident impulse control disorders in Parkinson's disease

Abstract

Objectives: Impulse control disorders (ICD) are commonly associated with dopamine replacement therapy (DRT) in patients with Parkinson's disease (PD). Our aims were to estimate ICD heritability and to predict ICD by a candidate genetic multivariable panel in patients with PD.

Methods: Data from de novo patients with PD, drug-naïve and free of ICD behaviour at baseline, were obtained from the Parkinson's Progression Markers Initiative cohort. Incident ICD behaviour was defined as positive score on the Questionnaire for Impulsive-Compulsive Disorders in PD. ICD heritability was estimated by restricted maximum likelihood analysis on whole exome sequencing data. 13 candidate variants were selected from the DRD2, DRD3, DAT1, COMT, DDC, GRIN2B, ADRA2C, SERT, TPH2, HTR2A, OPRK1 and OPRM1 genes. ICD prediction was evaluated by the area under the curve (AUC) of receiver operating characteristic (ROC) curves.

Results: Among 276 patients with PD included in the analysis, 86% started DRT, 40% were on dopamine agonists (DA), 19% reported incident ICD behaviour during follow-up. We found heritability of this symptom to be 57%. Adding genotypes from the 13 candidate variants significantly increased ICD predictability (AUC=76%, 95% CI (70% to 83%)) compared to prediction based on clinical variables only (AUC=65%, 95% CI (58% to 73%), p=0.002). The clinical-genetic prediction model reached highest accuracy in patients initiating DA therapy (AUC=87%, 95% CI (80% to 93%)). OPRK1, HTR2A and DDC genotypes were the strongest genetic predictive factors.

Conclusions: Our results show that adding a candidate genetic panel increases ICD predictability, suggesting potential for developing clinical-genetic models to identify patients with PD at increased risk of ICD development and guide DRT management.

Figure 1

ROC curves for prediction of ICD incidence in the whole population. The red ROC curve was plotted with clinical variables only (age, gender, DRT and duration of follow-up period). The blue ROC curve was plotted with clinical and genetic variables combined. The genetic variables consisted of genotype data on 13 preselected SNPs. p Value refers to AUC comparison of the two curves. AUC, area under the curve, DRT, dopamine replacement therapy; ICD, Impulse control disorders; ROC, receiver operating characteristic SNPs, single nucleotide polymorphisms.

Figure 2

ROC curves for prediction of ICD incidence in patients using dopamine agonists. The red ROC curve was plotted with clinical variables only (age, gender, DRT and duration of follow-up period). The blue ROC curve was plotted with clinical and genetic variables combined. The genetic variables consisted of genotype data on 13 preselected SNPs. p Value refers to AUC comparison of the two curves. AUC, area under the curve, DRT, dopamine replacement therapy; ICD, impulse control disorders; ROC, receiver operating characteristic SNPs, single nucleotide polymorphisms.