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Research paper
Clinical-genetic model predicts incident impulse control disorders in Parkinson's disease
  1. Julia Kraemmer1,2,
  2. Kara Smith3,
  3. Daniel Weintraub3,4,5,
  4. Vincent Guillemot1,
  5. Mike A Nalls6,
  6. Florence Cormier-Dequaire1,
  7. Ivan Moszer1,
  8. Alexis Brice1,
  9. Andrew B Singleton6,
  10. Jean-Christophe Corvol1
  1. 1Sorbonne 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
  2. 2Medical University of Vienna, Vienna, Austria
  3. 3Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  5. 5Corporal Michael J Crescenz Department of Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA
  6. 6Laboratory of Neurogenetics, National Institutes of Health, Bethesda, Maryland, USA
  1. Correspondence to Dr Jean-Christophe Corvol, CIC Neurosciences, ICM, Hôpital Pitié-Salpêtrière, 47-83 Bd de l'Hôpital, Paris 75013, France; jean-christophe.corvol{at}aphp.fr

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.

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