Open Access

Rapid motor progression of Parkinson’s disease associates with clinical and genetic variants

Ling-Xiao Cao1,2,Yong Jiang1,Ying-Shan Piao2,Yue Huang1,2,3,*
China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China
Department of Pharmacology, School of Medical Sciences, Faculty of Medicine & Health, UNSW Sydney, 2033 Sydney, Australia
DOI: 10.52586/5044 Volume 26 Issue 12, pp.1503-1512
Submited: 11 September 2021 Revised: 18 November 2021
Accepted: 26 November 2021 Published: 30 December 2021
*Corresponding Author(s):  
Yue Huang
Copyright: © 2021 The author(s). Published by BRI. This is an open access article under the CC BY 4.0 license (

Introduction: Parkinson’s disease (PD) is caused by the interplay of genetic and environmental factors during brain aging. About 90 single nucleotide polymorphisms (SNPs) have been recently discovered associations with PD, but whether they associate with the clinical features of PD have not been fully addressed yet. Methods: Clinical data of 365 patients with PD who enrolled in Parkinson’s Progression Markers Initiative (PPMI) study were obtained. Patients with rapid motor progression were determined through clinical assessments over five years follow-up. In addition, genetic information of 44 targeted SNPs was extracted from the genetic database of NeuroX for the same cohort. Logistic regression was used to analyze the genetic associations with rapid motor progression of PD. Results: Among 365 patients with PD, there are more male (66%) than female (34%). Seven SNPs (rs6808178, rs115185635, rs12497850, rs34311866, rs3793947, rs11060180, rs9568188) were associated with faster motor progression (p << 0.05), and only rs6808178 passed multiple comparison correction (p << 0.0011). In addition, the extended 44 SNPs with autonomic dysfunction reach a fair prediction of AUC at 0.821. Conclusion: Genetics and autonomic function factors contribute to the motor progression at the clinical initiation of PD.

Key words

Parkinson’s disease; Rapid motor progres-sion; Genes; Single nucleotide polymorphisms; Longitudi-nal study


[1] Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease. The Journal of the American Medical Association. 2020; 323: 548.

[2] Homayoun H. Parkinson Disease. Annals of Internal Medicine. 2018; 169: ITC33–ITC48.

[3] Kuhlman GD, Flanigan JL, Sperling SA, Barrett MJ. Predictors of health-related quality of life in Parkinson’s disease. Parkinsonism & Related Disorders. 2019; 65: 86–90.

[4] Simon DK, Tanner CM, Brundin P. Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology. Clinics in Geriatric Medicine. 2020; 36: 1–12.

[5] Xia R, Mao ZH. Progression of motor symptoms in Parkinson’s disease. Neuroscience Bulletin. 2012; 28: 39–48.

[6] Titova N, Qamar MA, Chaudhuri KR. The Nonmotor Features of Parkinson’s Disease. International Review of Neurobiology 2017; 132: 33–54.

[7] Tranchant C. Introduction and classical environmental risk factors for Parkinson. Revue Neurologique. 2019; 175: 650–651.

[8] Joshi N, Singh S. Updates on immunity and inflammation in Parkinson disease pathology. Journal of Neuroscience Research. 2018; 96: 379–390.

[9] Lunati A, Lesage S, Brice A. The genetic landscape of Parkinson’s disease. Revue Neurologique. 2018; 174: 628–643.

[10] Chang D, Nalls MA, Hallgrimsdottir IB, Hunkapiller J, van der Brug M, Cai F, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nature genetics. 2017; 49: 1511–1516.

[11] Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a metaanalysis of genome-wide association studies. The Lancet Neurol. 2019; 18: 1091–1102.

[12] Sun YM, Yu HL, Zhou XY, Xiong WX, Luo SS, Chen C, et al. Disease Progression in Patients with Parkin-Related Parkinson’s Disease in a Longitudinal Cohort. Movement Disorders. 2020; 36: 442–448.

[13] Zhao Y, Qin L, Pan H, Liu Z, Jiang L, He Y, et al. The role of genetics in Parkinson’s disease: a large cohort study in Chinese mainland population. Brain. 2020; 143: 2220–2234.

[14] Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. Neurobiology of Aging. 2016; 37: 209.e1–209.e7.

[15] Li M, Wang L, Liu JH, Zhan SQ. Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: Clinical Assessments, Biomarkers, and Treatment. The Chinese Medical Journal. 2018; 131: 966–973.

[16] Huang Y, Wang G, Rowe D, Wang Y, Kwok JB, Xiao Q, et al. SNCA Gene, but Not MAPT, Influences Onset Age of Parkinson’s Disease in Chinese and Australians. Biomed Research International. 2015; 2015: 135674.

[17] Huang Y, Rowe DB, Halliday GM. Interaction between alphasynuclein and tau genotypes and the progression of Parkinson’s disease. The Journal of Parkinson’s Disease. 2011; 1: 271–276.

[18] Wang G, Huang Y, Chen W, Chen S, Wang Y, Xiao Q, et al. Variants in the SNCA gene associate with motor progression while variants in the MAPT gene associate with the severity of Parkinson’s disease. Parkinsonism & Related Disorders. 2016; 24: 89–94.

[19] Alfradique-Dunham I, Al-Ouran R, von Coelln R, Blauwendraat C, Hill E, Luo L, et al. Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes. Neurology Genetics. 2021; 7: e557.

[20] Li C, Ou R, Chen Y, Gu X, Wei Q, Cao B, et al. Genetic Modifiers of Age at Onset for Parkinson’s Disease in Asians: a Genome-Wide Association Study. Movement Disorders. 2021; 36: 2077–2084.

[21] Liu G, Peng J, Liao Z, Locascio JJ, Corvol JC, Zhu F, et al. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease. Nature Genetics. 2021; 53: 787–793.

[22] Iwaki H, Blauwendraat C, Leonard HL, Kim JJ, Liu G, Maple-Grødem J, et al.. Genomewide association study of Parkinson’s disease clinical biomarkers in 12 longitudinal patients’ cohorts.Movement Disorders. 2019; 34: 1839–1850.

[23] Blauwendraat C, Leonard HL, Liu G, Maple-Grødem J, Corvol J, Pihlstrøm L, et al. Genetic risk of Parkinson disease and progression: an analysis of 13 longitudinal cohorts. Neurology Genetics. 2019; 5: e354.

[24] Tan MMX, Lawton MA, Jabbari E, Reynolds RH, Iwaki H, Blauwendraat C, et al. Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson’s Disease. Movement Disorders. 2021; 36: 424–433.

[25] Parkinson Progression Marker I. The Parkinson Progression Marker Initiative (PPMI). Progress in Neurobiology. 2011; 95: 629–635.

[26] Li K, Li S, Su W, Chen H. Diagnostic accuracy of REM sleep behaviour disorder screening questionnaire: a meta-analysis. Neurological Sciences. 2017; 38: 1039–1046.

[27] Rodriguez-Blazquez C, Forjaz MJ, Frades-Payo B, De Pedro-Cuesta J, Martinez-Martin P. Independent validation of the scales for outcomes in Parkinson’s disease-autonomic (SCOPAAUT). European Journal of Neurology. 2010; 17: 194–201.

[28] Weintraub D, Oehlberg KA, Katz IR, Stern MB. Test Characteristics of the 15-Item Geriatric Depression Scale and Hamilton Depression Rating Scale in Parkinson Disease. The American Journal of Geriatric Psychiatry. 2006; 14: 169–175.

[29] Shulman LM, Gruber-Baldini AL, Anderson KE, Fishman PS, Reich SG, Weiner WJ. The Clinically Important Difference on the Unified Parkinson’s Disease Rating Scale. Archives of Neurology. 2010; 67: 64–70.

[30] Schrag A, Dodel R, Spottke A, Bornschein B, Siebert U, Quinn NP. Rate of clinical progression in Parkinson’s disease. A prospective study. Movement Disorders. 2007; 22: 938–945.

[31] Paul KC, Schulz J, Bronstein JM, Lill CM, Ritz BR. Association of Polygenic Risk Score with Cognitive Decline and Motor Progression in Parkinson Disease. The Journal of the American Medical Association Neurology. 2018; 75: 360.

[32] Ghani M, Lang AE, Zinman L, Nacmias B, Sorbi S, Bessi V, et al. Mutation analysis of patients with neurodegenerative disorders using NeuroX array. Neurobiology of Aging. 2015; 36: 545.e9–545.e14.

[33] Nalls MA, Bras J, Hernandez DG, Keller MF, Majounie E, Renton AE, et al. NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases. Neurobiology of Aging. 2015; 36: 1605.e7–1605.e12.

[34] Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Research. 2019; 47: D607–D613.

[35] Pagano G, Ferrara N, Brooks DJ, Pavese N. Age at onset and Parkinson disease phenotype. Neurology. 2016; 86: 1400–1407.

[36] Wickremaratchi MM, Ben-Shlomo Y, Morris HR. The effect of onset age on the clinical features of Parkinson’s disease. European Journal of Neurology. 2009; 16: 450–456.

[37] De Pablo-Fernandez E, Tur C, Revesz T, Lees AJ, Holton JL, Warner TT. Association of Autonomic Dysfunction with Disease Progression and Survival in Parkinson Disease. The Journal of the American Medical Association Neurology. 2017; 74: 970.

[38] Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging. 2003; 24: 197–211.

[39] Boros FA, Maszlag-Török R, Vécsei L, Klivényi P. Increased level of NEAT1 long non-coding RNA is detectable in peripheral blood cells of patients with Parkinson’s disease. Brain Research. 2020; 1730: 146672.

[40] Kraus TFJ, Haider M, Spanner J, Steinmaurer M, Dietinger V, Kretzschmar HA. Altered Long Noncoding RNA Expression Precedes the Course of Parkinson’s Disease-a Preliminary Report. Molecular Neurobiology. 2017; 54: 2869–2877.

[41] Simchovitz A, Hanan M, Niederhoffer N, Madrer N, Yayon N, Bennett ER, et al. NEAT1 is overexpressed in Parkinson’s disease substantia nigra and confers drug-inducible neuroprotection from oxidative stress. The Federation of American Societies for Experimental Biology Journal. 2019; 33: 11223–11234.

[42] Ho D, Schierding W, Farrow S, Cooper AA, Kempa-Liehr AW, O’Sullivan JM. Machine learning identifies six genetic variants and alterations in the Heart Atrial Appendage as key contributors to PD risk predictivity. medRxiv. 2021. (in press)

[43] Langmyhr M, Henriksen SP, Cappelletti C, van de Berg WDJ, Pihlstrøm L, Toft M. Allele-specific expression of Parkinson’s disease susceptibility genes in human brain. Scientific Reports. 2021; 11: 504.

[44] Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, et al. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases alpha-synuclein aggregation. Proceedings of the National Academy of Sciences of the United States of America. 2017; 114: 2389–2394.

[45] Shu L, Liang D, Pan H, Xu Q, Guo J, Sun Q, et al. Genetic Impact on Clinical Features in Parkinson’s Disease: a Study on SNCA-rs11931074. Parkinson’s Disease. 2020; 2018: 2754541.

[46] Oosterveld LP, Allen JC, Ng EYL, Seah S, Tay K, Au W, et al. Greater motor progression in patients with Parkinson disease who carry LRRK2 risk variants. Neurology. 2015; 85: 1039–1042.

[47] Kurashige T, Takahashi T, Yamazaki Y, Hiji M, Izumi Y, Yamawaki T, et al. Localization of CHMP2B-immunoreactivity in the brainstem of Lewy body disease. Neuropathology. 2013; 33: 237–245.

[48] Tanikawa S, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K. Endosomal sorting related protein CHMP2B is localized in Lewy bodies and glial cytoplasmic inclusions in alphasynucleinopathy. Neuroscience Letters. 2012; 527: 16–21.

[49] Nagpal L, Fu C, Snyder SH. Inositol Hexakisphosphate Kinase-2 in Cerebellar Granule Cells Regulates Purkinje Cells and Motor Coordination via Protein 4.1N. The Journal of Neuroscience. 2018; 38: 7409–7419.

[50] Yoo T, Kim S, Yang SH, Kim H, Kim E, Kim SY. A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum. Molecular Autism. 2020; 11: 19.

[51] Deng X, Xiao B, Allen JC, Ng E, Foo JN, Lo YL, et al. Parkinson’s disease GWAS-linked Park16 carriers show greater motor progression. Journal of Medical Genetics. 2019; 56: 765–768.

Landmark/articles/materials/Supplementary matirals.docx
Share and Cite
Ling-Xiao Cao, Yong Jiang, Ying-Shan Piao, Yue Huang. Rapid motor progression of Parkinson’s disease associates with clinical and genetic variants. Frontiers in Bioscience-Landmark. 2021. 26(12); 1503-1512.