Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease

ObjectiveMutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinson's disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin.MethodsDetection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function.ResultsWe did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants.ConclusionsLarger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.     

Genetic variants of SNCA and LRRK2 genes are associated with sporadic PD susceptibility: A replication study in a Taiwanese cohort

BackgroundParkinson's disease (PD) is one of the most prevalent age-related neurodegenerative diseases and usually refers to a complex disorder with multiple genetic and environmental factors influencing disease risk. We here performed a gene-based case–control association study to scrutinize whether genetic variants in SNCA and LRRK2 genes could predispose to sporadic, late-onset form of PD in Taiwanese population.Methods17 Single Nucleotide Polymorphisms (SNPs) markers located within SNCA gene as well as the 16 SNP markers within LRRK2 gene were chosen for genotyping and evaluated their haplotype structure in a cohort of sporadic PD patients and control individuals.ResultsThis study showed that two SNPs near the promoter region (rs2301134 and rs2301135) of SNCA gene gave the greatest evidence for an association with PD (p ≤ 0.01) and a haplotype block with two SNPs in the 3′ UTR (rs356221 and rs11931074) revealed another evidence of association (p ≤ 0.02). For the LRRK2 gene, only R1628P variants of total 16 SNPs giving a marginal significant association with PD across the whole gene (p = 0.0058) and no haplotype block was constructed. Many genetic variants (A419V, I1122V, R1441C, R1441G, R1441H, Y1699C, M1869 V, M1869T, I2012T, G2019S, and I2020T) from previous reports were not detected in our cohort.ConclusionsWe have replicated a population-based PD association study in a collection of 626 cases and 473 control subjects and confirm that genetic variants of both SNCA and LRRK2 genes are associated with susceptibility to sporadic PD but in a different distribution.     

The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN

IntroductionMutations in the C19orf12 gene cause mitochondrial membrane protein associated neurodegeneration (MPAN), an autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). A limited number of patients with C19orf12 mutations, particularly those with adult onset of symptoms, have been reported.MethodsWe sequenced the entire coding region of C19orf12 in 15 Turkish adult probands with idiopathic NBIA. We also performed haplotype analysis in families with a recurrent C19orf12 mutation. Clinical features were collected using a standardized form.ResultsNine of our 15 probands (60%) carried the homozygous c.32C > T mutation in C19orf12 (predicted protein effect: p.Thr11Met). This homozygous mutation co-segregated with the disease in all affected relatives available for testing (16 homozygous subjects).Haplotypes across the C19orf12 locus were identical for a very small region, closest to the mutation, suggesting an old founder, or, two independent founders. The clinical phenotype was characterized by adult onset in most cases (mean 24.5 years, range 10–36), and broad spectrum, including prominent parkinsonism, pyramidal signs, psychiatric disturbances, cognitive decline, and motor axonal neuropathy, in various combinations. On T2- or susceptibility weighted-MRI images, all patients displayed bilateral hypointensities in globus pallidus and substantia nigra, without an eye-of-the-tiger sign; however, hyperintense streaking of the medial medullary lamina between the external and internal parts of globus pallidus was observed frequently.ConclusionThe C19orf12 p.Thr11Met mutation is frequent among adult Turkish patients with MPAN. These findings contribute to the characterization of this important NBIA form, and have direct implications for genetic testing of patients of Turkish origin.     

Genetic analysis of the fused in sarcoma gene in Chinese Han patients with Parkinson's disease

Background and purposeExome sequencing in a large essential tremor (ET) family identified a novel nonsense mutation (p.Q290X) in the fused in sarcoma gene (FUS) as the cause of this family. Because of the clinical overlap between ET and Parkinson's disease (PD), the role of FUS in an independent cohort of PD patients from China mainland was evaluated.MethodsThe entire coding region of FUS in 508 Chinese Han patients with PD and the identified variants in 633 normal controls were evaluated. A variant was further screened in an additional 382 controls for the frequency in our population.ResultsA novel variant c.696C > T (p.Y232Y) in 2 sporadic patients with PD and six variants (c.52C > A, p.P18T; c.52C > T, p.P18S; c.147C > A, p.G49G; c.291C > T, p.Y97Y; c.684C > T, p.G228G; c.1176G > A, p.M392I) without significant difference in genotypic and allelic distributions in our PD cohort were identified.ConclusionThe FUS gene is not a genetic risk factor for PD in the population of Chinese Han ethnicity.     

SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population

BackgroundSignificant efforts have been focused on investigating the contribution of common variants to Parkinson disease (PD) risk. Several independent GWAS and metanalysis studies have shown a genome-wide significant association of single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) regions. Here we investigated the role of SNCA and MAPT as PD susceptibility genes in a large Italian population of 904 patients and 891 controls. An evaluation of gene–gene and gene-environment interactions in association with PD was also attempted.MethodsThe SNCA Rep1 microsatellite was genotyped by a fluorescent PCR assay, whereas the SNPlex genotyping system was used to genotype 12 additional markers across the SNCA gene, and 2 SNPs tagging the risk MAPT H1 haplotype.ResultsSingle-marker analysis demonstrated nominal evidence of association for: i) the 261-bp-long allele of Rep1; ii) 7 SNPs in the SNCA region (top SNP: rs356186, P = 3.08 × 10^?04, intron 4); iii) both SNPs identifying the MAPT H1 haplotype (P = 4.63 × 10^?04 and P = 4.23 × 10^?04 for rs1800547 and rs9468, respectively). Moreover, we found a highly significant protective haplotype spanning ～83 kb from intron 4 to the 3′ end of SNCA (P = 1.29 × 10^?05).ConclusionsOur findings strongly confirm SNCA and MAPT as major PD susceptibility genes for idiopathic PD in the Italian population. Interaction analyses did not evidence either epistatic effects between the two loci or gene-environment interactions.     

Compound heterozygous variants in Wiskott-Aldrich syndrome like (WASL) gene segregating in a family with early onset Parkinson's disease

BackgroundKnowledge of genetic determinants in Parkinson's disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach is exploited in this study.MethodsInformative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of Parkinson's disease were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of variant(s) segregating with the phenotype were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest.ResultsTwo compound heterozygous variants, a rare missense (c.1139C > T:p.P380L) and a novel splice variant (c.1456 + 2 delTAGA, intron10) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and two affected siblings. WASL, a gene not previously linked to a human Mendelian disorder is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased reactive oxygen species tolerance in mutation carrying cells on Tetrabutylphosphonium hydroxide induction and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants.ConclusionWASL, with demonstrated functional relevance in neurons may be yet another strong candidate gene for autosomal recessive PD encouraging assessment of its contribution across populations.     

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.     

The PD-associated alpha-synuclein promoter Rep1 allele 2 shows diminished frequency in restless legs syndrome

Gain-of-function mutations of alpha-synuclein (SNCA) are known to trigger Parkinson’s disease (PD) with striatal dopaminergic deficits and a reduction of spontaneous movements. The longest size variant (allele 2) of the complex microsatellite repeat Rep1 within the SNCA gene promoter is known to confer a PD risk. We now observed this Rep1 allele 2 to show significantly decreased frequency in restless legs syndrome (RLS) in a genotyping study of 258 patients versus 235 healthy controls from Germany. Given that RLS is a disease with increased spontaneous movements and with increased striatal dopamine signaling, these novel data appear plausible. The scarcity of this alpha-synuclein gain-of-function variant in RLS might suggest that a low alpha-synuclein function via the SNARE complex in presynaptic vesicle release and neurotransmission of the striatum contributes to RLS pathogenesis.     

The role of the Ala746Thr variant in the ATP13A2 gene among Chinese patients with Parkinson’s disease

The association between idiopathic Parkinson’s disease (PD) and the ATP13A2 (PARK9) Ala746Thr variant, associated with Kufor-Rakeb syndrome, is controversial. We investigated this association in 69 patients with early onset PD (EOPD; ≦50 years of age), 192 patients with late onset PD (LOPD; >50 years of age), and 180 healthy controls in the Chinese population in Hong Kong. The presence of the Ala746Thr variant in the ATP13A2 locus was examined in all participants. We detected the heterozygous Ala746Thr variant in one healthy control (0.6%), one patient with EOPD (1.4%, p = 0.50), and one patient with LOPD (0.5%, p = 0.96). We suggest that the ATP13A2 Ala746Thr variant is not a common risk factor for PD in the Chinese population in Hong Kong.     

Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls

BackgroundAn increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts.MethodsWe screened the entire coding sequence and the 5′-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-ΔGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset.ResultsIn the case cohort, we identified a rare 5′-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-ΔGAG variants was 0.4%.ConclusionsOur study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia.     

A predictive model of neurodegeneration in idiopathic REM-sleep behavior disorder

ObjectiveTo investigate whether Parkinson's disease (PD) and dementia are competing risks in subjects with idiopathic rapid-eye-movement sleep behavior disorder (RBD).MethodsThe number of incidental PD cases observed in 11 longitudinal RBD studies was compared with the corresponding expected number as estimated by a simple mathematical model based on population parameters for PD age-of-onset.ResultsThe expected number of incidental PD cases exceeded observed PD cases (p-value < 0.001) but was in agreement with the sum of observed PD cases and observed mild cognitive impairment/dementia cases (p-value = 0.34). Sensitivity analyses confirmed the results.ConclusionIn the RBD population, PD and dementia cases are competing risks, suggesting that alpha-synuclein pathology occurs simultaneously in substantia nigra and neocortex. This observation has implications for the design and analysis of trials of neuroprotection.     

Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease

IntroductionUbiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown.MethodsUsing competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients.ResultsRepertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels.ConclusionsDifferences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.     

The lack of association between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms and schizophrenia in a group of Turkish population

IntroductionSchizophrenia is a complex neuropsychiatric disorder with deficits of multiple domains of cognitive functions, volition and emotions. Family and twin studies have provided cumulative evidence for the genetic basis of schizophrenia. The aetiolgy of this disease involves the interplay of multifactiorial inheritance operating on brain maturational processes and polygenic inheritance with some genes showing susceptibility at many genomic locations such as 22q and 11q.The catechol-O-methyltransferase (COMT-22q11) is an extensively studied candidate gene for schizophrenia. COMT acts as an enzymatic detoxicating barrier between the blood and other tissues regulating the amounts of active dopamine and norepinephrine in various parts of the brain and therefore to be associated with schizophrenia.The presence of a common functional single nucleotide polymorphism (SNP) in exon 4 [Guanine (G) Adenine (A); Val108/158Met], alters the enzymatic activity with a trimodal distribution of high-HH, intermediate-HL and low-LL activity alleles which appear to have association with schizophrenia.Brain-derived neurotrophic factor (BDNF-11q13) is a member of the nerve growth factor family working as a molecular regulator of neuronal development and plasticity. Molecules that are critical in the development and survival of neurons such as BDNF play a significant role in the neuropathology of schizophrenia. While upregulation of BDNF increases the neuronal cell size and synaptic plasticity, a functional polymorphism at codon 66 [G→A; Val66Met] down regulates this process and induces schizophrenia.ObjectiveIn the present study, our aim was to investigate the differences in allele frequencies between schizophrenic patients [n = 97 (51 men, 46 women)] and control group [n = 376 (228 men, 148 women)] subjects.ResultsWhen the control and schizophrenia groups were compared for BDNFVal66Met polymorphism, we did not find a significant difference between the study groups either for genotype (χ² = 3.370447, p > 0.05) or Val/Met haplotype analysis (χ² = 2.840264, p > 0.05). When a comparison was revealed for COMT-Val108/158Met polymorphism, no significant difference was detected among schizophrenia and control groups for genotype (χ² = 0.373330, p > 0.05) and Val/Met haplotype analysis (χ² = 0.339073, p > 0.05). When the control and study groups were compared for BDNFVal66Met–COMTVal108/158Met polymorphisms compound genotype and haplotype analyses, there was no significant difference between the two groups (χ² = 11.015; p > 0.05 and χ² = 3.191; p > 0.05), respectively.ConclusionOur results indicate that there is no association between schizophrenia and BDNF–COMT polymorphisms and haplotypes analysis. We also did not find an association between schizophrenia and BDNF–COMT compound genotype and haplotype analyses. Although our study is unique in Turkey as combining BDNF and COMT compound genotype–haplotype analyses, for a generalization of Turkish schizophrenia patient's susceptibility to schizophrenia; we need further studies with an enlarged cohort.     

Parkinson patient fibroblasts show increased alpha-synuclein expression

Parkinson's disease (PD) is a neurodegenerative movement disorder of advanced age with largely unknown etiology, but well documented tissue damage from oxidative stress. Increased α-synuclein (SNCA) expression is known to cause a rare form of PD, early-onset autosomal dominant PARK4. We have previously shown that loss-of-function mutations of the mitochondrial kinase PINK1 which cause the early-onset recessive PARK6 variant result in oxidative damage in patient fibroblasts. We now investigated the molecular chain of events from mitochondrial dysfunction to cell death which is largely unknown. Primary skin fibroblast cultures from patients were analysed for gene expression anomalies. In G309D-PINK1 patient fibroblasts, mainly genes regulated by oxidative stress, as well as genes encoding synaptic proteins such as SNCA showed altered expression. The induction of SNCA was also observed in control fibroblasts with knock-down of PINK1. The induction of SNCA expression was found to constitute a specific disease biomarker in sporadic PD patient fibroblasts. To understand the mechanism of this induction, we exposed control fibroblasts to oxidative, proteasomal and endoplasmic reticulum stress and were able to trigger the SNCA expression upregulation. Our data indicate that loss-of-function of PINK1 leads to enhanced alpha-synuclein expression and altered cell–cell contact. Alpha-synuclein induction might represent a common event for different variants of PD as well as a PD-specific trigger of neurodegeneration. We propose that the expression changes described might potentially serve as biomarkers that allow objective PD patient diagnosis in an accessible, peripheral tissue.     

α-Synuclein,alcohol use disorders,and Parkinson disease: A case–control study

Collaborative pooled analyses demonstrated that allele length variability of the dinucleotide repeat sequence within the α-synuclein gene promoter (SNCA REP1) is associated with Parkinson disease (PD) worldwide. Other studies demonstrated that variability in the SNCA promoter is also associated with alcohol use disorders, but not consistently. Yet other studies demonstrated that alcohol use disorders are inversely associated with PD, but not consistently. The aim of this study was to clarify the patterns of association between REP1 genotype, alcohol use disorders, and PD. Cases were recruited from the Department of Neurology of the Mayo Clinic in Rochester, MN. The controls included unaffected siblings and unrelated controls. We assessed alcohol use via a structured telephone interview and screened for alcohol use disorders using the CAGE questionnaire. REP1 genotyping was performed using an ABI 3730XL platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using conditional logistic regression models. We recruited 893 case–control pairs. There was an increasing risk of PD with increasing SNCA REP1 allele length (OR 1.18 for each REP1 genotype score unit, 95% CI 1.02–1.35; p = 0.02). There was a decreasing risk of PD with increasing CAGE score (p = 0.01). The association of REP1 score with PD remained significant after adjusting for CAGE score, and the association of CAGE score with PD remained significant after adjusting for REP1 score. There were no pairwise interactions. Our findings suggest that SNCA REP1 genotype and alcohol use disorders are independently associated with PD.     

Screening non-MAPT genes of the Chr17q21 H1 haplotype in Parkinson's disease

IntroductionThe microtubule-associated protein tau (MAPT) gene is considered a strong genetic risk factor for Parkinson's disease (PD) in Caucasians. MAPT is located within an inversion region of high linkage disequilibrium designated as H1 and H2 haplotype, and contains eight other genes which have been implicated in neurodegeneration. The aim of the current study was to identify common coding variants in strong linkage disequilibrium (LD) within the associated loci on chr17q21 harboring MAPT.MethodsSanger sequencing of coding exons in 90 Caucasian late-onset PD (LOPD) patients was performed. Specific gene sequencing for LRRC37A, LRRC37A2, ARL17A and ARL17B was not possible given the high homology, presence of pseudogenes and copy number variants that are in the region, and therefore four genes (NSF, KANSL1, SPPL2C, and CRHR1) were included in the analysis. Coding variants from these four genes that did not perfectly tag (r² = 1) the MAPT H1/H2 haplotype were genotyped in an independent replication series of Caucasian PD cases (N = 851) and controls (N = 730).ResultsIn the 90 LOPD cases we identified 30 coding variants. Eleven non-synonymous variants tagged the MAPT H1/H2 haplotype, including two SPPL2C variants (rs12185233 and rs12373123) that had high pathogenic combined annotation dependent depletion (CADD) scores of >20. In the replication series, the non-synonymous KANSL1 rs17585974 variant was in very strong LD with MAPT H1/H2 and had a high CADD score of 24.7.ConclusionWe have identified several non-synonymous variants across neighboring genes of MAPT that may warrant further genetic and functional investigation within the biological etiology of PD.     

Fatigue correlates with LRRK2 G2385R variant in Chinese Parkinson's disease patients

IntroductionFatigue is common in patients with Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) G2385R variant predisposes individuals to develop PD in China. The aim of this study was to evaluate whether the LRRK2 G2385R variant is associated with fatigue in patients with PD.MethodsFatigue was evaluated by the Parkinson Fatigue Scale (PFS) in 329 PD patients and 180 controls, a cut-off score of ≥3.3 was used to define the presence of fatigue. All the enrolled PD patients were assessed by a comprehensive battery of motor and non-motor questionnaires. PD patients were genotyped for the G2385R variant. Associations of fatigue with the clinical assessments and with the G2385R variant in PD patients were analyzed by logistic regression.ResultsFatigue frequency was 55.62%. A logistic regression model found that the female sex (OR = 10.477; 95%CI: 2.806–39.120; p < 0.001), motor function (OR = 1.060; 95%CI: 1.012–1.110; p = 0.013), sleep disturbance (OR = 0.943; 95%CI: 0.910–0.976; p = 0.001) and depression severity (OR = 0.843; 95%CI: 0.736–0.965; p = 0.013) collectively predict the presence of fatigue in PD patients. After adjustment for demographics and associated clinical factors, the G2385R variant was associated with an increased risk for the presence of fatigue (OR = 10.699; 95% CI = 2.387–47.958; p = 0.002) in the PD population in this study.ConclusionWe confirm that fatigue in PD patients is common, and we have strengthened the associations between fatigue and female sex, motor severity and non-motor symptoms, particularly depression and sleep disturbances. Overall, we found that carriers of the G2385R variant were more prone to fatigue than non-carriers in PD patients.