title: Tryptophan hydroxylase type 2 variants modulate severity and outcome of addictive behaviors in Parkinson's disease.
abstract: Impulse control disorders and compulsive medication intake may occur in a minority of patients with Parkinson's disease (PD). We hypothesize that genetic polymorphisms associated with addiction in the general population may increase the risk for addictive behaviors also in PD.
  
  
  
  Sixteen polymorphisms in candidate genes belonging to five neurotransmitter systems (dopaminergic, catecholaminergic, serotonergic, glutamatergic, opioidergic) and the BDNF were screened in 154 PD patients with addictive behaviors and 288 PD control subjects. Multivariate analysis investigated clinical and genetic predictors of outcome (remission vs. persistence/relapse) after 1 year and at the last follow-up (5.1 ± 2.5 years).
  
  
  
  Addictive behaviors were associated with tryptophan hydroxylase type 2 (TPH2) and dopamine transporter gene variants. A subsequent analysis within the group of cases showed a robust association between TPH2 genotype and the severity of addictive behaviors, which survived Bonferroni correction for multiple testing. At multivariate analysis, TPH2 genotype resulted the strongest predictor of no remission at the last follow-up (OR[95%CI], 7.4[3.27-16.78] and 13.2[3.89-44.98] in heterozygous and homozygous carriers, respectively, p < 0.001). The extent of medication dose reduction was not a predictor. TPH2 haplotype analysis confirmed the association with more severe symptoms and lower remission rates in the short- and the long-term (p < 0.005 for all analyses).
  
  
  
  The serotonergic system is likely to be involved in the pathophysiology of addictive behaviors in PD, modulating the severity of symptoms and the rate of remission at follow-up. If confirmed in larger independent cohorts, TPH2 genotype may become a useful biomarker for the identification of at-risk individuals.
authors.affiliation: Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy. Electronic address: roberto.cilia@gmail.com.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cilia
authors.affiliation: CNR - Neuroscience Institute, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Benfante
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Marabini
authors.affiliation: Nutrition and Dietetics Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cereda
authors.affiliation: Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Siri
authors.affiliation: Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.affiliation: Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.affiliation: CNR - Neuroscience Institute, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Fornasari
mesh_terms: D000328:Adult; D016739:Behavior, Addictive / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D004252:DNA Mutational Analysis; D015259:Dopamine Agents / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications* / Q000188:drug therapy / Q000523:psychology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014365:Tryptophan Hydroxylase / Q000235:genetics*
chemical_list: D015259:Dopamine Agents; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase
keywords: Addiction; Genetics; Impulse control disorders; Parkinson disease; Serotonin