Tryptophan hydroxylase type 2 variants modulate severity and outcome of addictive behaviors in Parkinson's disease. (August 2016)

• Record Type: Journal Article
• Authors: Cilia, Roberto; Benfante, Roberta; Asselta, Rosanna; Marabini, Laura; Cereda, Emanuele; Siri, Chiara; Pezzoli, Gianni; Goldwurm, Stefano; Fornasari, Diego
• Is Part Of: Parkinsonism & related disorders. Volume 29(2016)
• Page Start: 96
• Page End: 103
• Publication Date: 2016-08
• Subjects: Parkinson disease -- Impulse control disorders -- Genetics -- Addiction -- Serotonin; Parkinson's disease -- Periodicals; Movement disorders -- Periodicals; Movement Disorders -- Periodicals; Nerve Degeneration -- Periodicals; Nervous System Diseases -- Periodicals; Parkinson Disease -- Periodicals; Tremor -- Periodicals; Parkinson, Maladie de -- Périodiques; Parkinson's disease; 616.833
• DOI: 10.1016/j.parkreldis.2016.05.017
• Languages: English
• ISSNs: 1353-8020

Abstract

Abstract: Background: 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. Methods: 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). Results: 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). Conclusion: 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. Highlights: TPH2 genotype (mainly rs1352250) and TPH2 GGA haplotype are associated with increased severity of addictive symptoms. TPH2 variants interact with the BDNF to modulate the risk of abnormal behaviors. TPH2 genotype and haplotype are associated with reduced remission rate after 1 year and at the last follow-up (mean 5 years). TPH2 genotype influences long-term behavioral remission more than dopaminergic therapy adjustment.