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Background and purpose: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD‐related genes and determine the mutational spectrum of early‐onset PD in ethnic Chinese. Methods: In this study, whole‐exome sequencing and/or gene dosage analysis were performed in 704 early‐onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty‐six PD‐related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. Results: Eighty‐two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD‐related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi‐allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein‐truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late‐onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. Conclusions: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD. [ABSTRACT FROM AUTHOR]

Considering that I GBA i , I TMEM175 i , and I SNCA i are risk genes for both LBD and PD, it is noteworthy to investigate whether I BIN1 i and I APOE i are also associated with the risk of PD. Keywords: APOE; BIN1; Parkinson's disease; rare variant EN APOE BIN1 Parkinson's disease rare variant 698 701 4 04/15/22 20220501 NES 220501 Abbreviations GWAS genome-wide association study LBD Lewy body dementia PD Parkinson's disease Dear Editor, Recently, Chia et al. identified five risk genes for Lewy body dementia (LBD) in a genome-wide association study (GWAS) [1]. Similarly, a previous study identified that the I BIN1 i variant rs13403026 was associated with later AAO in I GBA i -associated PD [4], suggesting the potential role of I BIN1 i in regulating AAO in PD. [Extracted from the article]

Background: The association between inflammation and neurodegeneration has long been observed in parkinson's disease (PD) and multiple system atrophy (MSA). Previous genome-wide association studies (GWAS) and meta-analyses have identified several risk loci in inflammation-associated genes associated with PD. Objective: To investigate whether polymorphisms in some inflammation-associated genes could modulate the risk of developing PD and MSA in a Southwest Chinese population. Methods: A total of 2,706 Chinese subjects comprising 1340 PD, 483 MSA and 883 healthy controls were recruited in the study. Three polymorphisms (rs2074404 GG/GT/TT, rs17425622 CC/CT/TT, rs34043159 CC/CT/TT) in genes linked to inflammation in all the subjects were genotyped by using the Sequenom iPLEX Assay. Results: The allele G of WNT3 rs2074404 can increase risk on PD (OR: 1.048, 95% CI: 1.182–1.333, p = 0.006), exclusively in the LOPD subgroup (OR: 1.166, 95% CI:1.025–1.327, p = 0.019), but not in EOPD or MSA. And the recessive model analysis also demonstrated an increased PD risk in GG genotype of this locus (OR = 1.331, p = 0.007). However, no significant differences were observed in the genotype distributions and alleles of HLA-DRB5 rs17425622 and IL1R2 rs34043159 between the PD patients and controls, between the MSA patients and controls, or between subgroups of PD or MSA and controls. Conclusion: Our results suggested the allele G of WNT3 rs2074404 have an adverse effect on PD and particularly, on the LOPD subgroup among a Chinese population. [ABSTRACT FROM AUTHOR]

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson's disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence. [ABSTRACT FROM AUTHOR]

In addition, of the 232 patients who received DRT for more than 5 years, 69 patients (29.7%, 69/232) developed LIDs in the first 5 years of DRT. In a previous study, the incidence of LIDs has been reported to be 21.7% in Chinese LOPD patients [[5]], suggesting that the LIDs are common in EOPD, and EOPD patients are susceptible to the development of LIDs. Main text The levodopa-induced dyskinesias (LIDs) in Parkinson' disease (PD) patients during levodopa treatment can lead to significant disability. [Extracted from the article]