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Introduction: Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative diseases in the elderly. Recently, some variants of AD-causal genes (APP, PSEN1, PSEN2) have been reported in PD. In this study, we investigated the association between coding variants of AD-causal genes and PD in a large Chinese population cohort.Methods: We performed whole-exome sequencing (WES) on 1,917 patients with early-onset or familial PD and 1,652 controls, and whole-genome sequencing (WGS) on 1,962 sporadic late-onset PD and 1,279 controls. Genetic and phenotypic data were analyzed with regression analyses and the optimized sequence kernel association test. Further validation study was performed by Fisher's exact test.Results: We found that rs75733498 in the PSEN2 gene was significantly associated with early-onset or familial PD; however, no significant relationship was discovered between rs75733498 and sporadic late-onset PD. The result of the validation study still revealed a significant association between rs75733498 and PD. We observed a suggestive association with APP gene in early-onset or familial PD when considering damaging missense variants alone (p = 0.018) or combined with loss-of-function variants (p = 0.029). Further phenotypic analysis did not demonstrate any significant associations.Conclusion: Our results support a possible genetic contribution of AD-causal genes to PD. These findings warrant further genetic and functional confirmation, and more powerful association studies will better decipher the mechanisms of PD. [ABSTRACT FROM AUTHOR]

Moreover, four of six patients with biallelic mutations of I ATP10B i identified in the original study were early onset PD (EOPD; age-at-onset <= 50 years old), suggesting that it is worthwhile to further screen for I ATP10B i mutations in EOPD cases. Sir, We have read with great interest the article published recently in I Acta Neuropathologica i by Martin and colleagues [[2]], in which they reported that the biallelic loss-of-function mutations in the I ATP10B i , encodes a late endo-lysosomal lipid flippase, are associated with Parkinson's disease (PD). In conclusion, our data could not rule out the potential role of I ATP10B i biallelic variants in PD, but I ATP10B i may not play a major role in PD patients. [Extracted from the article]

The hydrogel actuated membrane in this paper is highly stretchable while having an electrically responsive output force. At a doping level of 0.6 g SA, the elongation at break of the hydrogel-driven membrane reached 3117% and the output force density reached 16.49 mN/g. In addition, the elastic modulus, tensile strength, and specific capacitance of the driving membrane reached the maximum values of 29.05 kPa, 907.24 kPa, and 452.8 mF/g at SA doping content of 0.75 g. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disease with inherent sex differences, and sex-determining region Y (SRY) is a gene located in the Y chromosome which encodes a transcription factor involving the regulation of the dopamine system. In this study, we investigated whether SRY variants were associated with PD in Chinese population. A total of 2058 male patients with PD and 1650 male control participants were recruited, and variants in SRY transcript and flanking regions were genotyped by whole-exome sequencing or whole-genome sequencing. Analysis of rare variants by the optimal sequence kernel association test showed no difference in variant burden of coding, 5′-noncoding and 3′-noncoding between the case and control group. In addition, of the 6 common variants identified, none showed a significant effect in altering PD risk in our population using logistic regression. Our results suggested SRY variants were not associated with the risk of PD in Chinese population. [ABSTRACT FROM AUTHOR]

Background and purpose: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. Methods: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat‐primed PCR and GC‐rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno‐associated virus (AAV)‐mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. Results: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p‐value = 0.29). Skin biopsy showed P62‐positive intranuclear NOTCH2NLC‐polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa‐NOTCH2NLC‐(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. Conclusions: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. A significant overlap in clinical features, epidemiology, imaging, and pathology suggests that PD and ET may also share common genetic risk factors. Previous studies have only assessed a limited number of ET‐associated genes in PD patients and vice versa. Consequently, the genetic association between PD and ET remains incompletely characterized. In this study, we systematically investigated a potential association between rare coding variants in ET‐associated genes and PD, in a relatively large Chinese population cohort. Methods: To investigate the genetic association between ET and PD, we performed the sequence kernel association testing (SKAT‐O) to explore the variant burden of 33 ET‐associated genes, using whole‐exome sequencing (WES) data from 1494 early‐onset PD (EOPD) patients and 1357 control subjects from mainland China. Results: We report that rare loss‐of‐function and damaging missense variants of TNEM4 are suggestively associated with EOPD (P = 0.026), damaging missense variants of TNEM4 alone are also suggestively associated with EOPD (P = 0.032). No other rare damaging variants in ET‐related genes were significantly associated with EOPD. Interpretation: This is the first systematic analysis of ET‐associated genes in EOPD. The suggestive association between TNEM4 and EOPD provides new evidence for a genetic link between ET and PD. [ABSTRACT FROM AUTHOR]

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset Parkinson's disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson's disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson's disease, 242 probands from families with autosomal-dominant Parkinson's disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson's disease-associated genes occurred more frequently in the autosomal-recessive Parkinson's disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson's disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson's disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson's disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson's disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson's disease-associated genes. Our data highlight the importance of genetic testing in Parkinson's disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Inflammation has been demonstrated to be involved in Parkinson's disease (PD) pathogenesis. There were evidences that the disturbance of the protective function of IL-10 gene contributed to PD. In our study, haplotype analyses were conducted of IL-10 rs1800871 and rs1800872 on 371 PD patients. Because the two SNPs exposed significant linkage disequilibrium demonstrated by Haploview software, we included 177 carriers of both rs1800871 and rs1800872 and 190 noncarriers in clinical phenotype analyses. As to nonmotor symptoms, the score of the gastrointestinal dysfunction domain in Nonmotor Symptom Scale (NMSS) was lower in the carrier group of both SNPs than in the noncarrier group in PD patients (SC: −0.198, p:0.023). Other nonmotor symptoms reflected by relevant rating scales showed negative results. As to comorbidity, no significant statistical significance was observed between the two SNPs and Charlson Comorbidity Index (CCI). In conclusion, we found less severe gastrointestinal dysfunctions of both IL-10 rs1800871 and rs1800872 carriers than noncarriers in PD. [ABSTRACT FROM AUTHOR]

SNCA-rs11931074 had been demonstrated to be strongly correlated with PD risk. However, there was lack of comprehensive analysis of SNCA-rs11931074-related clinical features which may help explain clinical heterogeneity of PD. In our study, we performed association analyses on the relationship between SNCA-rs11931074 and motor symptoms, nonmotor symptoms, and comorbidities in PD. 611 rs11931074 carriers and 113 rs11931074 noncarriers were enrolled. In the clinical phenotype analyses, the Unified Parkinson's Disease Rating Scale part II (UPDRS II) and part III (UPDRS III) scores of rs11931074 carriers were lower than those of noncarriers (SC: −0.083, p=0.035; SC: −0.140, p≤0.001). The Charlson Comorbidity Index (CCI) score of carriers was lower than that of noncarriers (SC: −0.097, p=0.009). No significant statistical differences were found between the variant and other clinical features such as motor complications and nonmotor symptoms. The SNCA-rs11931074 carriers may present with more benign clinical profiles than noncarriers with less severe motor symptoms and comorbidity burden. [ABSTRACT FROM AUTHOR]

Highlights • a large sample of 721 PD patients of Chinese origin. • motor symptoms, non-motor symptoms and co-morbidities were analyzed in our study. • the relationship between the variants and clinical symptoms were analyzed. Abstract LRRK2 is the most common genetic cause of PD. G2385R and R1628 P variants are the most common variants of LRRK2 in Chinese populations. Consensus on the clinical features of G2385R and R1628 P related PD has not been reached yet, although it had been widely studied. In our study, genotype analyses were conducted on 721 PD patients of Chinese origin. A total of 62 G2385R carriers, 32 R1628 P carriers and 623 idiopathic PD patients underwent the following clinical feature analysis. Motor symptoms, non-motor symptoms and co-morbidities were the targeted features to be analyzed. As a result, Neither the G2385R nor the R1628 P carriers showed significant clinical feature differences when compared to the idiopathic PD patients, so did the comparison between the G2385R and the R1628 P carriers. In conclusion, the clinical features of PD patients with LRRK2 G2385R or R1628 P variants were similar to those of idiopathic PD. [ABSTRACT FROM AUTHOR]

With the development of wearable devices, the application of non-invasive wearable devices to monitor sweat in real time is the most important for human health. Here, a paper-based microfluidic chip for monitoring of sweat loss during exercise is proposed. Highly absorbent rice paper is selected as the paper-based material, and the capillary action of the paper base is used to actively adsorb sweat, and it can be used repeatedly. As the electrode material, the conductive cloth has good tensile properties and bending resistance, which ensures that the change of resistance is caused by the amount of sweat entering. Other materials of the chip are highly hydrophobic, ensuring that all sweat will be absorbed by the paper base. The sweat volume monitored by the microfluidic chip in real time is 0.5μl-225μl. Compared with rigid electrodes and wet electrodes, the application of flexible electrodes allows the chip to fit well with the skin, the ECG waveform is clearer and has greater amplitude, and the EMG is smoother and has a greater signal-to-noise ratio. [Display omitted] • With the development of wearable devices, non-invasive wearable devices have developed into a hot spot. • Here, a paper-based microfluidic chip for monitoring of sweat loss during exercise is proposed. • The high bending properties of the chip ensure that the resistance change is caused by the amount of sweat. • Use hydrophobic materials to ensure that sweat is absorbed by the paper base, and monitor the sweat volume of 0.5μl-225μl. • The flexible electrode makes the chip fit well with the skin, the ECG waveform is clearer, and the EMG is smoother. [ABSTRACT FROM AUTHOR]

Increasing the surface area of active materials is a crucial approach to enhance the capacity of supercapacitors. In this study, we present an interdigitated supercapacitor featuring a double-layer active material prepared using a sacrificial layer method. The replacement of the insulating substrate with a gel electrolyte facilitates ion motion between the active electrodes. Finite element analysis (FEA) and electrochemical experiments confirm that the utilization of double-layer active material can significantly improve the capacity (1.5–1.85 times higher than traditional structures). The electrochemical performance of the three active materials has been significantly improved after using the double-layer active material structure, which proves that the method in this paper has strong material compatibility. Furthermore, an interdigital supercapacitor (ISC) is fabricated using electrodes with double-layer active material through the sacrificial layer method and its electrochemical performance is evaluated. At a scan rate of 10 mV·s-1, ISC exhibits an impressive area-specific capacitance as high as 68.4 mF·cm-2. Remarkably, ISC can maintain stable power output even under extreme deformation and fatigue testing conditions. This strategy involving interdigitated supercapacitors with double-layer active materials prepared via the sacrificial layer method presents a promising solution for flexible energy storage devices. • Use sacrificial layer method to remove the substrate. • A double-layer active material structure with increased capacity is proposed. • Replace the insulating substrate with a gel electrolyte. [ABSTRACT FROM AUTHOR]

• The susceptibility gene of Parkinson's disease: focus on LIN28A gene. • The burden analysis of rare variants in LIN28A gene between PD patients and healthy controls. • Impact of LIN28A gene on neural development and Parkinson's disease. Parkinson's disease (PD) is a neurodegenerative disease caused by aging, environmental and genetic factors, and many susceptibility genes have been found to increase the risk for PD. Lin28a, an RNA binding protein, is expressed prominently in neural progenitor cells. The expression of Lin28a is decreased gradually with neural differentiation and is implicated in oncogenesis, glucose metabolism, neurogenesis, and neurogliogenesis. However, few genetic studies have explored the association between rare variants of the LIN28A gene and PD yet. Our study recruited 3,879 PD patients and 2,931 controls, and they were divided into two cohorts, including the EOPD & FPD cohort and the LOPD cohort, separately sequenced by whole-exome sequencing and whole-genome sequencing. We found nine rare nonsynonymous variants in the coding region of the LIN28A gene, but the rare variants of this gene were not enriched in PD patients in both cohorts. Thence, our study did not support the association between the LIN28A gene and the PD risk in the Chinese mainland population. [ABSTRACT FROM AUTHOR]

Background: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. Objectives: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross‐sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. Methods: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face‐to‐face interviews biennially. Results: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD‐MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early‐onset PD (EOPD, age at onset ≤50 years) and late‐onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa‐induced dyskinesias in women. Conclusions: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Flexible sensors are an important part of flexible electronic devices, and its application often relies on external power sources. However, traditional commercial batteries require repeated charging, lack of flexibility and potential leakage of electrolyte contamination, which seriously hinder the wearable smart electronic devices' develop of comfortable and portable integration. To overcome this key challenge. This paper combines energy harvesting technology, distributed energy storage devices and flexible electronics. This proposes a modular layout of friction nanogenerator (TENG), miniature solid-state supercapacitor (MSSC) and strain sensor. Three of modular components are constructed on a thermoplastic polyamide film. The basic conductive network is prepared through screen printing technique and graphene multiwall carbon nanotubes (G-MWCNTs) conductive inks. The TENG module is used to collect low-frequency and high-entropy mechanical energy from the surrounding environment for conversion into AC electrical energy. The MSSC module is used to store the electrical energy generated by the TENG and to continuously power the back-end flexible electronics. The strain sensor module has an asymmetric interlaced double-arc snake rib conductive structure inspired by the spotted snake. It enables multi-dimensional strain detection and ultra-sensitive sensing performance. Finally, as a concept proof, the prepared TENG, MSSC and strain sensors are composed to form a self-powered multimode distributed flexible sensing device. It can be used for human health monitoring in the areas of knuckle, elbow, hip and heel nodes. [Display omitted] • This proposes a modular layout of friction nanogenerator (TENG), miniature solid-state supercapacitor (MSSC) and strain sensor. The TENG outputs a maximum voltage of 15.36 V, a shortage current of 0.57 μA and a transferred charge of 5.70 nC. MSSC has a high area ratio capacitance of 7.09 mF cm-2. Capacitance retention up to 96.68% after 5000 volt-amp cycles. The strain sensor uses only 0.1061nW of power at a 0.001 V operating voltage. • The strain sensor module has an asymmetric interlaced double-arc snake rib conductive structure inspired by the spotted snake. It enables multi-dimensional strain detection and ultra-sensitive sensing performance. The sensor proposed in this paper achieves strain gauge factor (GF) of 6300.75 and 435% wide sensing range response. [ABSTRACT FROM AUTHOR]

The PLA2G6 gene has been identified as a causative gene for autosomal recessive early-onset dystonia-parkinsonism. Possible association was reported between single heterozygous PLA2G6 mutation and the risk of Parkinson's disease (PD), which, however, remained inconclusive. To clarify the effect of heterozygous PLA2G6 variants on the risk of PD, a total of 3710 patients with PD and 2636 controls of Chinese mainland population were recruited and genotyped by whole-exome sequencing or whole-genome sequencing. Variants in the PLA2G6 coding region were extracted and subjected to burden analysis using the optimal sequence kernel association test. In total, we identified 86 rare heterozygous variants in the PLA2G6 coding region, whereas no significant difference was found between cases and controls. Therefore, we found no supportive evidence for heterozygous PLA2G6 variants being a risk factor for PD in Chinese mainland population. [ABSTRACT FROM AUTHOR]

Flexible electrodes are usually well-matched to the substrate as the core component of flexible electronics technology. However, when large deformation occurs, the conductive layer of flexible electrodes can mechanically fracture due to insufficient mechanical properties, leading to the failure of flexible electronic devices. Improving the mechanical properties of flexible electrodes is essential for the development of flexible electronics. Herein, a flexible electrode with a serpentine shape tetra-chiral structure is designed and fabricated via screen-printed process based on existing tetra-chiral structure. The research demonstrates that the serpentine tetra-chiral structure can improve the mechanical properties of the flexible electrode and the maximum tensile stress is reduced by 87.19 % relative to existing tetra-chiral structure. The flexible electrode is still conductive when the strain of that is 70 %, and the resistance is only 5 Ω and 4.4 Ω, respectively, at a bending angle of 180° and following 1000 times fold cycles. In addition, the flexible electrodes fabricated in this paper are utilized to realize the collection of ECG signals and pulse signals, showing greater potential in biological signal monitoring. The strategy proposed here is expected to maintain electrodes' original functions under repeated use and complex deformation. [Display omitted] • An electrode with a serpentine four-chiral structure is proposed, which shows excellent performance in detecting physiological signals. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disorder with multiple factors contributing to disease pathogenesis. Previous studies implicated the involvement of the transcription factor hypoxia inducible factor 1 alpha (HIF1A) in PD through its transcriptional regulation of PD-associated genes. This study uses molecular inversion probes (MIPs) followed by high-throughput sequencing for the genetic analysis of HIF1A in a large cohort including 1692 ethnic Han Chinese PD patients and 1419 neurologically normal control subjects matched for age, gender, and ethnicity. Common HIF1A variant rs11549465 was found to be associated with increased late-onset PD (LOPD) risk (OR (95%CI) = 1.531(1.068-2.194), P = 0.03828 for trend test, P = 0.03948 for analyses using the allelic model and P = 0.04196 for logistic regression analyses (sex + age as covariates)). Though the gene-based variants burden test is negative, seven rare non-synonymous, predicted-pathogenic point variants were identified. In conclusion, our study further indicates that HIF1A plays a role in PD pathogenesis. [ABSTRACT FROM AUTHOR]

[Display omitted] • A serpentine structure with low curvature is designed to improve stability. • By sacrificing the substrate, the stretchability of the SSC electrode is improved. • The patterned electrolyte thin film was prepared. • The supercapacitor with high tensile strength and high stability was prepared. Optimizing electrode structures is a promising solution for wearable electronics and flexible power sources. Nevertheless, there are still significant challenges in how to get rid of the constraints of the substrate and electrolyte on the electrode structure, thereby reducing the impact of such constraints on the elongation of supercapacitors and stabilizing the electrochemical output. In this work, a serpentine structure of low curvature (SSLC) was designed and fabricated by comparing the effect of the curvature of the turning structure on the performance of the serpentine structure. The superiority of SSLC electrodes over existing electrode structures is verified using finite element analysis (FEA) and stability experiments. Further, the SSLC electrode is used for physiological signal detection (ECG, EMG, GSR), showing excellent stability and low electrode–skin contact impedance, which is better than the medical wet electrode. A high-stretch supercapacitor (SSC) was prepared by sacrificing the substrate of the SSLC electrode and integrating the patterned electrolyte film. When the scan rate is 10 mV·s−1, the area specific capacitance of SSC is as high as 197.9 mF·cm−2. Under extreme deformation conditions (stretch 100%, bend 180°, twist 180°) SSC can maintain stable output. And after 10,000 charge–discharge cycles, the SSC can still output 91.96% of the initial power stably, indicating that the prepared SSC has high stretchability and stability. With highly stretchable and stable low-curvature serpentine structure electrodes, the SSC coupled with patterned electrolyte films and sacrificial substrate electrodes in this paper offer a promising solution for stretchable flexible power supplies and wearable electronics. [ABSTRACT FROM AUTHOR]

Background. GBA gene had been proved to be a crucial gene to the risk of PD. Numerous studies had discussed about the unique clinical characteristics of PD patients with GBA carriers (GBA + PD). However, there was lack of updated comprehensive analysis on the topic. In order to clarify the association between GBA variants and the clinical phenotypes of PD, we conducted this comprehensive meta-analysis. Method. Medline, Embase, and Cochrane were used to perform the searching. Strict selection criteria were followed in screening for new published articles or data. Revman 5.3 software was applied to perform the total statistical analysis, and funnel plots in the software were used to assess the publication biases. Results. A total of 26 articles including 931 GBA + PD and 14861 GBA noncarriers of PD (GBA − PD) were involved in the final meta-analysis, and 14 of them were either newly added publications or related data newly analyzed compared with the version published in 2015. Then, a series of symptoms containing depression, orthostatic hypotension, motor fluctuation, wearing-off, and freezing were newly analyzed due to more articles eligible. Besides, clinical features like family history, AAO, UPDRS-III, H-Y, and dementia previously analyzed were updated with new data added. Significant statistical differences were found in wearing-off, family history, AAO, UPDRS-III, and dementia (OR: 1.14, 1.65; MD: −3.61, 2.17; OR: 2.44; p: 0.03, <0.00001, <0.00001, 0.003, and <0.00001). Depression was slightly associated with GBA + PD (OR: 1.47; p: 0.04). Clinical symptoms such as H-Y, orthostatic hypotension, motor fluctuation, and freezing did not feature GBA + PD. Conclusion. Our results demonstrated that there were unique clinical features in GBA + PD which can help the management of the whole duration of PD patients. [ABSTRACT FROM AUTHOR]

REP1 is a polymorphic dinucleotide repeat sequence located in the promoter region of the SNCA gene (OMIM 163890). Opinions regarding the interaction between the various REP1 alleles and Parkinson’s disease (PD) or its phenotypes have been inconsistent and have thus far not been comprehensively analyzed. In this study, we searched Medline, Embase and Cochrane databases as well as the Chinese-language Wanfang and CNKI databases using strict inclusion and exclusion criteria and conducted our analysis using Revman 5.3 software. Our search produced 28 articles describing REP1 alleles and their associated PD risks and 8 articles which discussed the relationship between REP1 variation and PD phenotypes. We found that the 265-, 269-, and 271-bp alleles of REP1 (using the nomenclature established by Xia et al.) increased the risk of PD (OR: 1.81, 1.05, 1.17; p : 0.0002, 0.003, 0.002) while the 267-bp allele decreased PD risk (OR: 0.86, p : <0.00001) when taking all populations into account. By ethnicity, we observed an obvious population heterogeneity in the effects of various alleles, where the 269-, 271-, and 273-bp alleles increased PD risk (OR: 1.06, 1.22, 1.89; p : 0.001, 0.003, 0.001) and the 267-bp allele decreased PD risk (OR: 0.85; p : <0.00001) in Caucasian populations, and the 263- and 265-bp alleles increased the risk of PD (OR: 2.22, 2.03; p : 0.03, 0.0002) and the 267- and 273-bp alleles decreased PD risk (OR: 0.90, 0.78; p : 0.02, 0.03) in Asian populations. We also determined that the 267-, 269-, and 271-bp alleles occurred the most frequently, although the frequency distribution varied among different ethnicities. Phenotypic analysis demonstrated that PD patients carrying the 271-bp allele were prone to early onset PD (OR: 1.75, p : 0.02) while the 267-bp had the opposite effect (OR: 0.81; p : 0.01). [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disease with a relatively unclear etiology. Previous studies have shown that N6-methyladenosine (m6A) is a vital RNA modification enriched in brain tissue, and that the genes involved in m6A modification are implicated in various neurologic diseases. Here, we conducted a comprehensive genetic analysis using targeted sequencing with molecular inversion probes (MIPs) to identify m6A-modification genes (including METTL3, METTL14, WTAP, FTO, ALKBH5, YTHDF1, YTHDF2, YTHDF3, HNRNPC, and ELAVL1) in a total of 1647 sporadic PD patients and 1372 controls of Han Chinese origin. PD patients were divided into early-onset PD (EOPD) and late-onset PD (LOPD) based on whether the onset of motor symptoms occurred before or after 50 years of age. Rare variants were subjected to gene-based burden tests and common variants were subjected to single-variant association analyses. As a result, we identified 214 rare variants in all 10 m6A-modification genes and 16 common variants in 7 genes. Gene-wise association analyses of rare variants in each m6A-modification gene did not achieved a p value of less than 0.05 in either total cohorts or 2 age groups. In fact, p values greater than 0.05 were found when conducting single-variant association analyses on common variants of these genes between PD and control patients. Our comprehensive analyses of m6A-modification genes suggest that there is no significant association between these 10 m6A-modification genes and the risk of sporadic PD. • A relatively large cohort of Chinese PD patients and controls were included. • A comprehensive analysis on the 10 m6A genes in PD and controls using MIPs. • No significant association between these 10 m6A genes and the risk of sporadic PD. [ABSTRACT FROM AUTHOR]

DNA methylation is an important regulatory mechanism of Parkinson's disease (PD). To investigate the relationship between DNA methylation and hydroxymethylation genes and PD, we performed gene-targeted sequencing using molecular inversion probes in a Chinese PD population. We sequenced 12 genes related to DNA methylation and hydroxymethylation in 1657 patients and 1394 control subjects. We conducted genewise association analyses of rare variants detected in the present study and identified the TET1 gene as important in PD (p = 0.0037738, 0.013, 0.019521 (b.collapse test, variable threshold test, and skat-o test, respectively; sex + age as covariates). However, no positive results were observed when conducting association analyses on common variants in these genes. We performed a comprehensive analysis of associations between variants of DNA methylation and hydroxymethylation genes and PD, resulting in determination that TET1 might play a role in PD. • A large Chinese PD cohort (1657 patients and 1394 controls) were included. • A comprehensive analysis on the 12 DNA methylation/hydroxymethylation genes in PD with target sequencing using molecular inversion probes (MIPs). • TET1 might play a role in PD. [ABSTRACT FROM AUTHOR]