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J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1106-11. doi: 10.1136/jnnp-2015-312848. Epub 2016 Apr 13.

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

Author information

1
Sorbonne Universités, UPMC Univ Paris 06, and INSERM UMRS_1127 and CIC_1422, and CNRS UMR_7225, and AP-HP, and ICM, Département des maladies du système nerveux and Département de Génétique, Hôpital Pitié-Salpêtrière, Paris, France Medical University of Vienna, Vienna, Austria.
2
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA Corporal Michael J Crescenz Department of Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
4
Sorbonne Universités, UPMC Univ Paris 06, and INSERM UMRS_1127 and CIC_1422, and CNRS UMR_7225, and AP-HP, and ICM, Département des maladies du système nerveux and Département de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
5
Laboratory of Neurogenetics, National Institutes of Health, Bethesda, Maryland, USA.

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.

PMID:
27076492
PMCID:
PMC5098340
DOI:
10.1136/jnnp-2015-312848
[Indexed for MEDLINE]
Free PMC Article

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