title: Clinical-genetic model predicts incident impulse control disorders in Parkinson's disease.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Julia
authors.initials: J
authors.lastname: Kraemmer
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weintraub
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Guillemot
authors.affiliation: Laboratory of Neurogenetics, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Cormier-Dequaire
authors.affiliation: 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.
authors.forename: Ivan
authors.initials: I
authors.lastname: Moszer
authors.affiliation: 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.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Laboratory of Neurogenetics, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: 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.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004185:Disability Evaluation; D007174:Disruptive, Impulse Control, and Conduct Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics*; D015259:Dopamine Agents / Q000009:adverse effects* / Q000627:therapeutic use; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015999:Multivariate Analysis; D010300:Parkinson Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents