TY - JOUR
T1 - Tryptophan hydroxylase type 2 variants modulate severity and outcome of addictive behaviors in Parkinson's disease
AU - Cilia, Roberto
AU - Benfante, Roberta
AU - Asselta, Rosanna
AU - Marabini, Laura
AU - Cereda, Emanuele
AU - Siri, Chiara
AU - Pezzoli, Gianni
AU - Goldwurm, Stefano
AU - Fornasari, Diego
PY - 2015/12/30
Y1 - 2015/12/30
N2 - 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.
AB - 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.
KW - Addiction
KW - Genetics
KW - Impulse control disorders
KW - Parkinson disease
KW - Serotonin
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U2 - 10.1016/j.parkreldis.2016.05.017
DO - 10.1016/j.parkreldis.2016.05.017
M3 - Article
AN - SCOPUS:84969915710
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
SN - 1353-8020
ER -