Comprehensive variant analysis of phospholipase A2 superfamily genes in large Chinese Parkinson' s disease cohorts.

To clarify the genetic role of phospholipase A2 (PLA2) genes in Parkinson's disease (PD), we performed a genetic association study in large Chinese population cohorts using next-generation sequencing. In this study, we analyzed both rare and common variants of 38 phospholipase A2 genes in two large cohorts. We detected 1558 and 1115 rare variants in these two cohorts, respectively. In both cohorts, we observed suggestive associations between specific subgroups and the risk of PD. At the single-gene level, several genes (PLA2G2D, PLA2G12A, PLA2G12B, PLA2G4F, PNPLA1, PNPLA3, PNPLA7, PLA2G7, PLA2G15, PLAAT5, and ABHD12) are suggestively associated with PD. Meanwhile, 364 and 2261 common variants were identified in two cohorts, respectively. Our study has expanded the genetic spectrum of the PLA2 family genes and suggested potential pathogenetic roles of PLA2 superfamily in PD.

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration.

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.

Genetic analysis of transcription factors in dopaminergic neuronal development in Parkinson's disease.

BACKGROUND: Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson's disease (PD) risk factors; however, no comprehensive analyses of these genes in patients with PD have been undertaken. Therefore, we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD. METHODS: Whole-exome sequencing (WES) was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls. Additionally, whole-genome sequencing (WGS) was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls. RESULTS: We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts, respectively. Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD. However, the significance did not pass the Bonferroni correction. Meanwhile, 72 and 1730 common variants were found in the WES and WGS cohorts, respectively. Unfortunately, single-variant logistic association analyses did not identify significant associations between common variants and PD. CONCLUSIONS: Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients. However, we highlight the complexity of PD and the need for extensive research elucidating its etiology.

Mutational spectrum and clinical features of GBA1 variants in a Chinese cohort with Parkinson's disease.

GBA1 variants are important risk factors for Parkinson's disease (PD). Most studies assessing GBA1-related PD risk have been performed in European-derived populations. Although the coding region of the GBA1 gene in the Chinese population has been analyzed, the sample sizes were not adequate. In this study, we aimed to investigate GBA1 variants in a large Chinese cohort of patients with PD and healthy control and explore the associated clinical characteristics. GBA1 variants in 4034 patients and 2931 control participants were investigated using whole-exome and whole-genome sequencing. The clinical features of patients were evaluated using several scales. Regression analysis, chi-square, and Fisher exact tests were used to analyze GBA1 variants and the clinical symptoms of different groups. We identified 104 variants, including 8 novel variants, expanding the spectrum of GBA1 variants. The frequency of GBA1 variants in patients with PD was 7.46%, higher than that in the control (1.81%) (P < 0.001, odds ratio [OR] = 4.38, 95% confidence interval [CI]: 3.26-5.89). Among patients, 176 (4.36%) had severe variants, 34 (0.84%) carried mild variants, three (0.07%) had risk variants, and 88 (2.18%) carried unknown variants. Our study, for the first time, found that p.G241R (P = 0.007, OR = 15.3, 95% CI: 1.25-261.1) and p.S310G (P = 0.005, OR = 4.86, 95% CI: 1.52-28.04) variants increased the risk of PD. Patients with GBA1 variants exhibited an earlier onset age and higher risk of probable rapid-eye-movement sleep behavior disorder, olfactory dysfunction, depression, and autonomic dysfunction than patients without GBA1 variants.

Evaluation of the role of FMR1 CGG repeat allele in Parkinson's disease from the Chinese population.

Objective: There is controversial evidence that FMR1 premutation or "gray zone" (GZ) allele (small CGG expansion, 45-54 repeats) was associated with Parkinson's disease (PD). We aimed to explore further the association between FMR1 CGG repeat expansions and PD in a large sample of Chinese origin. Methods: We included a cohort of 2,362 PD patients and 1,072 controls from the Parkinson's Disease and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) in this study and conducted repeat-primed polymerase chain reaction (RP-PCR) for the size of FMR1 CGG repeat expansions. Results: Two PD patients were detected with FMR1 premutation (61 and 56 repeats), and the other eleven PD patients were detected with the GZ allele of FMR1 CGG repeat expansions. Those thirteen PD patients responded well to levodopa and were diagnosed with clinically established PD. Specifically, one female PD patient with GZ allele was also found with premature ovarian failure. However, compared to healthy controls, we found no significant enrichment of GZ allele carriers in PD patients or other subgroups of PD cases, including the subgroups of female, male, early-onset, and late-onset PD patients. Furthermore, we did not find any correlation between the FMR1 gene CGG repeat sizes and age at onset of PD. Conclusion: It suggested that FMR1 premutation was related to PD, but the GZ allele of FMR1 CGG repeat expansions was not significantly enriched in PD cases of Chinese origin. Further larger multiple ethnic studies are needed to determine further the role of the FMR1 GZ allele in PD.

Genetic analysis of dystonia-related genes in Parkinson's disease.

Objective: Parkinson's disease (PD) and dystonia are two closely related movement disorders with overlaps in clinical phenotype. Variants in several dystonia-related genes were demonstrated to be associated with PD; however, genetic evidence for the involvement of dystonia-related genes in PD has not been fully studied. Here, we comprehensively investigated the association between rare variants in dystonia-related genes and PD in a large Chinese cohort. Methods: We comprehensively analyzed the rare variants of 47 known dystonia-related genes by mining the whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 3,959 PD patients and 2,931 healthy controls. We initially identified potentially pathogenic variants of dystonia-related genes in patients with PD based on different inheritance models. Sequence kernel association tests were conducted in the next step to detect the association between the burden of rare variants and the risk for PD. Results: We found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including COL6A3 and TH. Additionally, we identified 180 deleterious variants in dominant dystonia-related genes based on computational pathogenicity predictions and four of which were considered as potentially pathogenic variants (p.W591X and p.G820S in ANO3, p.R678H in ADCY5, and p.R458Q in SLC2A1). A gene-based burden analysis revealed the increased burden of variant subgroups of TH, SQSTM1, THAP1, and ADCY5 in sporadic early-onset PD, whereas COL6A3 was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction. Conclusion: Our findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of COL6A3 and TH genes in PD is highlighted.

Evaluating the association between DNM1L variants and Parkinson's disease in the Chinese population.

Introduction: Parkinson's disease (PD) is a progressive movement disorder caused by a loss of dopaminergic neurons. Previous studies have highlighted the importance of mitochondria dynamics in the pathogenesis of PD. Dynamin-1-like (DNM1L) is a gene that encodes dynamin-related protein 1 (DRP1), a GTPase essential for proper mitochondria fission. In the present study, we evaluated the relationship between DNM1L variants and PD in the Chinese population. Methods: A total of 3,879 patients with PD and 2,931 healthy controls were recruited and burden genetic analysis combined with high-throughput sequencing was applied. Results: We identified 23 rare variants in the coding region of DNM1L, while no difference in variant burden was shown between the cases and controls. We also identified 201 common variants in the coding and flanking regions and found two significant SNPs, namely, rs10844308 and rs143794289 [odds ratio (OR) = 1.220 and 0.718, p = 0.025 and 0.036, respectively]. We also performed a meta-analysis to correlate the two SNPs with PD risk. However, none of the common variants was significant using logistic regression. Conclusion: Despite the critical role of DRP1, our study did not support the relationship between DNM1L variants and PD risk in the Chinese population.

Characteristics of fatigue in Parkinson's disease: A longitudinal cohort study.

Objective: To assess the prevalence, evolution, clinical characteristics, correlates and predictors of fatigue as well as to investigate the influence of comorbid fatigue on the longitudinal changes in motor and non-motor symptoms over a 2-year longitudinal follow-up period in a large cohort of patients with Parkinson's disease (PD). Materials and methods: A total of 2,100 PD patients were enrolled from the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC), and their motor and non-motor symptoms were assessed biennially using comprehensive scales, including the 16-item Parkinson Fatigue Scale (PFS-16). Each PD patient was categorized as PD with or without fatigue on the basis of a cut-off mean PFS-16 score of 3.3. Results: The prevalence of fatigue in our cohort was 36.8%. Compared to PD patients without fatigue, PD patients with fatigue were more likely to be older, have a longer disease duration, and higher baseline levodopa equivalent daily dose (all p < 0.05). Moreover, PD patients with fatigue showed more severe motor and non-motor phenotypes than those without fatigue. Overall, high total Unified Parkinson's Disease Rating Scale (UPDRS) score (odds ratio [OR] = 1.016, 95% confidence interval [CI]: 1.009-1.024), Non-Motor Symptoms Scale score (OR = 1.022, 95% CI: 1.015-1.029), postural instability and gait difficulty (PIGD) subtype (OR = 1.586, 95% CI: 1.211-2.079), presence of excessive daytime sleepiness (EDS; OR = 1.343, 95% CI: 1.083-1.666), and wearing-off (OR = 1.282, 95% CI: 1.023-1.607) were significantly associated with fatigue in PD patients (all p < 0.05). High total UPDRS score at baseline (OR = 1.014, 95% CI: 1.002-1.027, p = 0.028) increased the risk of developing fatigue during follow-up. Although significant, the odds ratios were low and confidence intervals were narrow. Analysis of disease progression showed significant group differences in motor and non-motor symptoms. In comparison with the never-fatigue group, the persistent-fatigue group showed significantly greater progression in motor, autonomic dysfunction, sleep, depression and cognitive symptoms (all p < 0.05). Conclusion: Increased disease severity, presence of the PIGD subtype, EDS, and wearing-off were associated with fatigue in PD patients. Significant subgroup-level differences were observed in the progression of motor and non-motor symptoms across different fatigue subgroups of PD patients.

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population.

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (Pcombined = 1.47 × 10-9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10-8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (rb) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14-0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (rg = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.

Evaluating the Genetic Role of Circadian Clock Genes in Parkinson's Disease.

Increasing evidence suggests that circadian dysfunction is related to Parkinson's disease (PD). However, the role of circadian clock genes in PD is still poorly understood. This study aimed to illustrate the association between genetic variants of circadian clock genes and PD in a large Chinese population cohort. Ten circadian clock genes were included in this study. Whole-exome sequencing (WES) was conducted in 1997 early-onset or familial PD patients and 1652 controls (WES cohort), and whole-genome sequencing (WGS) was conducted in 1962 sporadic late-onset PD patients and 1279 controls (WGS cohort). Analyses were completed using the optimized sequence kernel association test and regression analyses. In the burden analysis of the circadian clock gene set, we found suggestive significant associations between the circadian clock genes and PD in the WES cohort when considering missense, damaging missense (Dmis), and deleterious variants. Moreover, the burden analysis of single genes revealed suggestive significant associations between PD and the loss-of-function variants of the CRY1 gene, missense, Dmis, and deleterious variants of the PER1 gene, and Dmis and deleterious variants of the PER2 gene in the WES cohort. Rare variants in the WGS cohort and all common variants in the WGS and WES cohorts were unrelated to PD. Phenotypic analysis indicated that deleterious variants of the PER1 gene were associated with dyskinesia in the WES cohort. Our study provides evidence of a potential link between circadian clock genes and PD from a genetic perspective.

Screen-printed highly stretchable and stable flexible electrodes with a negative Poisson's ratio structure for supercapacitors.

Flexible power sources are crucial to developing flexible electronic systems; nonetheless, the current poor stretchability and stability of flexible power sources hinder their application in such devices. Accordingly, the stretchability and fatigue stability of flexible power sources are crucial for the practical application of flexible electronic systems. In this work, a flexible electrode with an arc-shaped star concave negative Poisson's ratio (NPR) structure is fabricated through the screen printing process. Using the combination of finite element analysis (FEA) and tensile tests, it is proven that the arc-shaped star concave NPR electrode can effectively reduce the maximum tensile stress and increase the maximum elongation (maximum elongation 140%). Furthermore, the flexible electrodes prepared in this study are assembled into all-solid-state symmetric supercapacitors (SSCs), and their electrochemical properties are tested. The SSC prepared in this study has a high areal capacitance of 243.1 mF cm-2. It retains 89.25% of its initial capacity after 5000 times of folding and can maintain a stable output even in extreme deformation, which indicates that the SSC prepared in this study has excellent stability. The SSC with the advantages mentioned above obtained in this study is expected to provide new opportunities to develop flexible electronic systems.

Association between NOTCH3 gene and Parkinson's disease based on whole-exome sequencing.

Objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. Previous studies have established a link between NOTCH3 variants and Parkinson's disease (PD) in terms of neuropathology and clinical characteristics. In this study, we aimed to explore the role of NOTCH3 gene in PD in a large Chinese cohort. Methods: A total of 1,917 patients with early-onset or familial PD and 1,652 matched controls were included. All variants were divided into common or rare types by minor allele frequency (MAF) at a threshold of 0.01 (MAF > 0.01 into common variants and others into rare variants). Common variants were subjected to single-variant tests by PLINK, then gene-based analyses were used for rare variants with the optimized sequence kernel association test (SKAT-O). For genotype-phenotype correlation assessment, regression models were conducted to compare clinical features between the studied groups. Results: Three common variants (rs1044006, rs1043997, and rs1043994) showed a nominal protective effect against PD. However, none of these SNPs survived Bonferroni correction. The results in the validation cohort revealed a significant but opposite association between these variants and PD. The gene-based analyses of rare variants showed no significant associations of NOTCH3 with PD. Although we did not find significant associations in the following genotype-phenotype analysis, the higher clinical scores of motor symptoms in NOTCH3-variant carriers were of interest. Conclusion: Our results indicated that NOTCH3 gene may not play an important role in the early-onset or familial PD of Chinese population.

Subtyping of early-onset Parkinson's disease using cluster analysis: A large cohort study.

Background: Increasing evidence suggests that early-onset Parkinson's disease (EOPD) is heterogeneous in its clinical presentation and progression. Defining subtypes of EOPD is needed to better understand underlying mechanisms, predict disease course, and eventually design more efficient personalized management strategies. Objective: To identify clinical subtypes of EOPD, assess the clinical characteristics of each EOPD subtype, and compare the progression between EOPD subtypes. Materials and methods: A total of 1,217 patients were enrolled from a large EOPD cohort of the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) between January 2017 and September 2021. A comprehensive spectrum of motor and non-motor features were assessed at baseline. Cluster analysis was performed using data on demographics, motor symptoms and signs, and other non-motor manifestations. In 454 out of total patients were reassessed after a mean follow-up time of 1.5 years to compare progression between different subtypes. Results: Three subtypes were defined: mild motor and non-motor dysfunction/slow progression, intermediate and severe motor and non-motor dysfunction/malignant. Compared to patients with mild subtype, patients with the severe subtype were more likely to have rapid eye movement sleep behavior disorder, wearing-off, and dyskinesia, after adjusting for age and disease duration at baseline, and showed a more rapid progression in Unified Parkinson's Disease Rating Scale (UPDRS) total score (P = 0.002), UPDRS part II (P = 0.014), and III (P = 0.001) scores, Hoehn and Yahr stage (P = 0.001), and Parkinson's disease questionnaire-39 item version score (P = 0.012) at prospective follow-up. Conclusion: We identified three different clinical subtypes (mild, intermediate, and severe) using cluster analysis in a large EOPD cohort for the first time, which is important for tailoring therapy to individuals with EOPD.

Tesla Valve-Based Flexible Microhybrid Chip with Unidirectional Flow Properties.

Flexible microfluidic chips have good application prospects in situations with easy bending and complex curvature. An important factor affecting the flexible microfluidic chip is its structural complexity. For example, the hybrid chip includes flow channels, mixing chambers, and one-way valves. How to achieve the same function with as few structures as possible has become an important research topic at present. In this paper, a Tesla valve micromixer with unidirectional flow characteristics is presented. A passive laminar flow Tesla valve micromixer is fabricated through 3D printing technology and limonene dissolution method. The main process is as follows: First of all, high impact polystyrene (HIPS) material was employed to make the Tesla valve channel mold. Second, the channel mold was dissolved in the limonene solvent. The mold of Tesla micromixer is made of HIPS material, the mixing experiment displace that the Tesla valve micromixer is characterized by unidirectional flow compared with the common T-shaped planar channel. At the same time, the 5-AAC Tesla valve micromixer can increase the mixing efficiency to 87%. By using four different groove structures and different flow rates of the mixing effect experiment, the conclusion is that the mixing efficiency of the 6-AAC Tesla valve micromixer is up to 0.89 when the flow rate is 2 mL/min. The results manifest that the Tesla valve structure can effectively improve the mixing efficiency.

Association of rare PPARGC1A variants with Parkinson's disease risk.

BACKGROUND: Recent researches on Parkinson's disease (PD) pathogenesis discovered the correlation between PD and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) dysfunction and reduction of PPARGC1A gene expression. Hence, we detected PPARGC1A rare variants to clarify their effect on PD risk in a large population of PD patients in mainland China. METHODS: We applied whole-exome sequencing (WES) to 1917 patients with early-onset or familial PD and 1652 controls (WES cohort), and whole-genome sequencing (WGS) to 1962 patients with sporadic late-onset PD and 1279 controls (WGS cohort). To identify PPARGC1A rare variants, we used burden analysis to assess the relationship between PPARGC1A rare variants and PD susceptibility. RESULTS: 30 rare missense variants in the cohort WES and 21 missense variants in the cohort WGS have been detected in the study and PPARGC1A missense variants are significantly associated with early-onset and familial PD susceptibility in our study (P = 0.012), which supports evidence that PPARGC1A rare variants are involved in the onset of early-onset and familial PD. CONCLUSIONS: The study suggested that PPARGC1A rare variants may contribute to the risk of early-onset and familial PD.

Genetic Analysis of Six Transmembrane Protein Family Genes in Parkinson's Disease in a Large Chinese Cohort.

Objectives: Parkinson's disease (PD) is a neurodegenerative disorder with the manifestation of motor symptoms and non-motor symptoms. Previous studies have indicated the role of several transmembrane (TMEM) protein family genes in PD pathogenesis. Materials and Methods: In order to better investigate the genetic role of PD-related TMEM protein family genes in PD, including TMEM230, TMEM59, TMEM108, TMEM163, TMEM175, and TMEM229B, 1,917 sporadic early onset PD (sEOPD) or familial PD (FPD) patients and 1,652 healthy controls were analyzed by whole-exome sequencing (WES) while 1,962 sporadic late-onset PD (sLOPD) and 1,279 healthy controls were analyzed by whole-genome sequencing (WGS). Rare and common variants for each gene were included in the analysis. Results: One hundred rare damaging or loss of function variants of six genes were found at the threshold of MAF < 0.1%. Three rare Dmis variants of TMEM230 were specifically identified in PD. Rare missense variants of TMEM59 were statistically significantly associated with PD in the WES cohort, indicating the role of TMEM59 in FPD and sEOPD. Rare missense variants of TMEM108 were suggestively associated with PD in the WGS cohort, indicating the potential role of TMEM108 in sLOPD. The rare variant of the other three genes and common variants of six genes were not significantly associated with PD. Conclusion: We performed a large case-control study to systematically investigate the role of several PD-related TMEM protein family genes in PD. We identified three PD-specific variants in TMEM230, the significant association of TMEM59 with FPD, and sEOPD and the suggestive association of TMEM108 with sLOPD.

Genetic Analysis of HSP40/DNAJ Family Genes in Parkinson's Disease: a Large Case-Control Study.

Molecular chaperones were reported to play an important role in PD pathogenesis. Recent studies revealed the association of several HSP40/DNAJ family genes with PD, but no genetic analysis of all the DNAJ family genes in PD has been conducted. To systematically analyze the genetic impact of all the DNAJ family genes in PD, we performed genetic analysis for these genes in a large case-control study. We analyzed the rare variants in 49 DNAJ family genes from 3879 PD patients and 2931 healthy controls by whole-exome sequencing and whole-genome sequencing. All rare missense variants and the subgroups of rare damaging missense (Dmis) and loss-of-function (LoF) variants were gathered to test the accumulated association of these variants in each gene with PD. In total, 1617 rare nonsynonymous variants of DNAJ family genes with minor allele frequency less than 1% were identified in our cohort. We identified 82 rare missense variants for DNAJC26 in sporadic early-onset PD (sEOPD) or familial PD (FPD), and 17 Dmis and one LoF variant were detected among them. Gene-based burden analysis showed that the rare Dmis variants alone or Dmis plus LoF variants together of DNAJC26 were significantly enriched in PD patients. We also found suggestive associations of DNAJB2 and DNAJC18 with PD in sEOPD or FPD and DNAJC2, DNAJC10, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 with PD in sporadic late-onset PD. In conclusion, rare missense variants of DNAJC26 were significantly enriched in FPD or sEOPD. Moreover, DNAJB2, DNAJC2, DNAJC10, DNAJC18, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 were suggestively associated with PD.

Profiling the Genome-Wide Landscape of Short Tandem Repeats by Long-Read Sequencing.

Background: Short tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases and the regulation of gene expression. Long-read sequencing (LRS) offers a potential solution to genome-wide STR analysis. However, characterizing STRs in human genomes using LRS on a large population scale has not been reported. Methods: We conducted the large LRS-based STR analysis in 193 unrelated samples of the Chinese population and performed genome-wide profiling of STR variation in the human genome. The repeat dynamic index (RDI) was introduced to evaluate the variability of STR. We sourced the expression data from the Genotype-Tissue Expression to explore the tissue specificity of highly variable STRs related genes across tissues. Enrichment analyses were also conducted to identify potential functional roles of the high variable STRs. Results: This study reports the large-scale analysis of human STR variation by LRS and offers a reference STR database based on the LRS dataset. We found that the disease-associated STRs (dSTRs) and STRs associated with the expression of nearby genes (eSTRs) were highly variable in the general population. Moreover, tissue-specific expression analysis showed that those highly variable STRs related genes presented the highest expression level in brain tissues, and enrichment pathways analysis found those STRs are involved in synaptic function-related pathways. Conclusion: Our study profiled the genome-wide landscape of STR using LRS and highlighted the highly variable STRs in the human genome, which provide a valuable resource for studying the role of STRs in human disease and complex traits.

The Chinese Parkinson's Disease Registry (CPDR): Study Design and Baseline Patient Characteristics.

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.