Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease
S. Jesús
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorM. T. Periñán
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorC. Cortés
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Search for more papers by this authorD. Buiza-Rueda
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorD. Macías-García
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorA. Adarmes
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorL. Muñoz-Delgado
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Search for more papers by this authorM. Á. Labrador-Espinosa
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorC. Tejera-Parrado
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Search for more papers by this authorCorresponding Author
M. P. Gómez-Garre
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Correspondence: P. Mir and M. P. Gómez-Garre, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Hospital Universitario Virgen del Rocío, Av. Manuel Siurot s/n. 41013, Seville, Spain (tel.: +34 954923039; fax: +34 955923101; e-mail: [email protected] and [email protected]).
Search for more papers by this authorCorresponding Author
P. Mir
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Correspondence: P. Mir and M. P. Gómez-Garre, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Hospital Universitario Virgen del Rocío, Av. Manuel Siurot s/n. 41013, Seville, Spain (tel.: +34 954923039; fax: +34 955923101; e-mail: [email protected] and [email protected]).
Search for more papers by this authorS. Jesús
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorM. T. Periñán
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorC. Cortés
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Search for more papers by this authorD. Buiza-Rueda
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorD. Macías-García
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorA. Adarmes
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorL. Muñoz-Delgado
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Search for more papers by this authorM. Á. Labrador-Espinosa
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Search for more papers by this authorC. Tejera-Parrado
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Search for more papers by this authorCorresponding Author
M. P. Gómez-Garre
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Correspondence: P. Mir and M. P. Gómez-Garre, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Hospital Universitario Virgen del Rocío, Av. Manuel Siurot s/n. 41013, Seville, Spain (tel.: +34 954923039; fax: +34 955923101; e-mail: [email protected] and [email protected]).
Search for more papers by this authorCorresponding Author
P. Mir
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology/Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Correspondence: P. Mir and M. P. Gómez-Garre, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Hospital Universitario Virgen del Rocío, Av. Manuel Siurot s/n. 41013, Seville, Spain (tel.: +34 954923039; fax: +34 955923101; e-mail: [email protected] and [email protected]).
Search for more papers by this authorAbstract
Background and purpose
Impulse control disorders (ICDs) are frequent in Parkinson’s disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD.
Methods
We included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease for ICDs screening. Motor, nonmotor, and treatment-related features were evaluated according to the presence of ICDs. Twenty-one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs.
Results
Impulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical–genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms.
Conclusions
Polymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient’s genetic background to identify individuals at risk for ICDs.
Supporting Information
| Filename | Description |
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| ene14590-sup-0001-Supinfo.docxWord document, 22.1 KB |
Table S1. Selected genetic variants. Figure S1. Distribution of impulse control disorders subtypes in the population with impulse control disorders. Figure S2. Distribution of impulse control disorders by gender. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Weintraub D, David AS, Evans AH, Grant JE, Stacy M. Clinical spectrum of impulse control disorders in Parkinson's disease. Mov Disord 2015; 30: 121–127.
- 2Weintraub D, Papay K, Siderowf A. Parkinson's Progression Markers I. Screening for impulse control symptoms in patients with de novo Parkinson disease: a case-control study. Neurology 2013; 80: 176–180.
- 3Cilia R, Ko JH, Cho SS, et al. Reduced dopamine transporter density in the ventral striatum of patients with Parkinson's disease and pathological gambling. Neurobiol Dis 2010; 39: 98–104.
- 4Kreek MJ, Nielsen DA, Butelman ER, LaForge KS. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 2005; 8: 1450–1457.
- 5Robbins TW, Arnsten AF. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci 2009; 32: 267–287.
- 6Eisenegger C, Knoch D, Ebstein RP, Gianotti LR, Sandor PS, Fehr E. Dopamine receptor D4 polymorphism predicts the effect of L-DOPA on gambling behavior. Biol Psychiatry 2010; 67: 702–706.
- 7Retz W, Rosler M, Supprian T, Retz-Junginger P, Thome J. Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD-related psychopathology. J Neural Transm (Vienna) 2003; 110: 561–572.
- 8Cilia R, Benfante R, Asselta R, et al. Tryptophan hydroxylase type 2 variants modulate severity and outcome of addictive behaviors in Parkinson's disease. Parkinsonism Relat Disord 2016; 29: 96–103.
- 9Cormier-Dequaire F, Bekadar S, Anheim M, et al. Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease. Mov Disord 2018; 33: 1878–1886.
- 10Lee JY, Lee EK, Park SS, et al. Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson's disease. Mov Disord 2009; 24: 1803–1810.
- 11Vallelunga A, Flaibani R, Formento-Dojot P, Biundo R, Facchini S, Antonini A. Role of genetic polymorphisms of the dopaminergic system in Parkinson's disease patients with impulse control disorders. Parkinsonism Relat Disord 2012; 18: 397–399.
- 12Lee JY, Jeon BS, Kim HJ, Park SS. Genetic variant of HTR2A associates with risk of impulse control and repetitive behaviors in Parkinson's disease. Parkinsonism Relat Disord 2012; 18: 76–78.
- 13Kraemmer J, Smith K, Weintraub D, et al. Clinical-genetic model predicts incident impulse control disorders in Parkinson's disease. J Neurol Neurosurg Psychiatry 2016; 87: 1106–1111.
- 14Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for impulsive-compulsive disorders in parkinson's disease-rating scale. Mov Disord 2012; 27: 242–247.
- 15Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov Disord 2010; 25: 2649–2653.
- 16Reese MG, Eeckman FH, Kulp D, Haussler D. Improved splice site detection in Genie. J Comput Biol 1997; 4: 311–323.
- 17Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37: e67.
- 18Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010; 67: 589–595.
- 19Papay K, Mamikonyan E, Siderowf AD, et al. Patient versus informant reporting of ICD symptoms in Parkinson's disease using the QUIP: validity and variability. Parkinsonism Relat Disord 2011; 17: 153–155.
- 20Antonini A, Barone P, Bonuccelli U, Annoni K, Asgharnejad M, Stanzione P. ICARUS study: prevalence and clinical features of impulse control disorders in Parkinson's disease. J Neurol Neurosurg Psychiatry 2017; 88: 317–324.
- 21Garcia-Ruiz PJ, Martinez Castrillo JC, Alonso-Canovas A, et al. Impulse control disorder in patients with Parkinson's disease under dopamine agonist therapy: a multicentre study. J Neurol Neurosurg Psychiatry 2014; 85: 840–844.
- 22Biundo R, Weis L, Abbruzzese G, et al. Impulse control disorders in advanced Parkinson's disease with dyskinesia: The ALTHEA study. Mov Disord 2017; 32: 1557–1565.
- 23Balash Y, Mordechovich M, Shabtai H, Giladi N, Gurevich T, Korczyn AD. Subjective memory complaints in elders: depression, anxiety, or cognitive decline? Acta Neurol Scand 2013; 127: 344–350.
- 24Corvol JC, Artaud F, Cormier-Dequaire F, et al. Longitudinal analysis of impulse control disorders in Parkinson disease. Neurology 2018; 91: e189–e201.
- 25Berry MD, Juorio AV, Li XM, Boulton AA. Aromatic L-amino acid decarboxylase: a neglected and misunderstood enzyme. Neurochem Res 1996; 21: 1075–1087.
- 26Agrawal A, Verweij KJ, Gillespie NA, et al. The genetics of addiction-a translational perspective. Transl Psychiatry 2012; 2: e140.
- 27Gray JC, MacKillop J. Genetic basis of delay discounting in frequent gamblers: examination of a priori candidates and exploration of a panel of dopamine-related loci. Brain Behav 2014; 4: 812–821.
- 28Ma JZ, Beuten J, Payne TJ, Dupont RT, Elston RC, Li MD. Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence. Hum Mol Genet 2005; 14: 1691–1698.
- 29Zhang H, Ye Y, Wang X, Gelernter J, Ma JZ, Li MD. DOPA decarboxylase gene is associated with nicotine dependence. Pharmacogenomics 2006; 7: 1159–1166.
- 30Devos D, Lejeune S, Cormier-Dequaire F, et al. Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease. Parkinsonism Relat Disord 2014; 20: 170–175.
- 31Lohle M, Mangone G, Wolz M, et al. Functional monoamine oxidase B gene intron 13 polymorphism predicts putaminal dopamine turnover in de novo Parkinson's disease. Mov Disord 2018; 33: 1496–1501.
- 32Erga AH, Dalen I, Ushakova A, et al. Dopaminergic and opioid pathways associated with impulse control disorders in Parkinson's disease. Front Neurol 2018; 9: 109.
- 33Krishnamoorthy S, Rajan R, Banerjee M, et al. Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients. Parkinsonism Relat Disord 2016; 30: 13–17.
- 34Rajan R, Krishnan S, Sarma G, Sarma SP, Kishore A. Dopamine Receptor D3 rs6280 is associated with aberrant decision-making in Parkinson's disease. Mov Disord Clin Pract 2018; 5: 413–416.
- 35Castro-Martinez XH, Garcia-Ruiz PJ, Martinez-Garcia C, et al. Behavioral addictions in early-onset Parkinson disease are associated with DRD3 variants. Parkinsonism Relat Disord 2018; 49: 100–103.
- 36Zainal Abidin S, Tan EL, Chan SC, et al. DRD and GRIN2B polymorphisms and their association with the development of impulse control behaviour among Malaysian Parkinson's disease patients. BMC Neurol 2015; 15: 59.
- 37Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982; 143: 29–36.
- 38Redensek S, Flisar D, Kojovic M, et al. Genetic variability of inflammation and oxidative stress genes does not play a major role in the occurrence of adverse events of dopaminergic treatment in Parkinson's disease. J Neuroinflammation 2019; 16: 50.
