A systematic review of associations between common SNCA variants and clinical heterogeneity in Parkinson's disease.
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ABSTRACT:
SUBMITTER: Pedersen CC
PROVIDER: S-EPMC8249472 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is increasing evidence of the contribution of genetic susceptibility to the etiology of Parkinson's disease (PD). Genetic variations in the SNCA gene are well established by linkage and genome-wide association studies. Positive associations of single nucleotide polymorphisms (SNPs) in SNCA and increased risk for PD were found. However, the role of SNCA variants in individual traits or phenotypes of PD is unknown. Here, we reviewed the current literature and identified 57 studies, performed in fourteen different countries, that investigated SNCA variants and susceptibility to PD. We discussed the findings based on environmental factors, history of PD, clinical outcomes, and ethnicity. In conclusion, SNPs within the SNCA gene can modify the susceptibility to PD, leading to increased or decreased risk. The risk associations of some SNPs varied among samples. Of notice, no studies in South American or African populations were found. There is little information about the effects of these variants on particular clinical aspects of PD, such as motor and nonmotor symptoms. Similarly, evidence of possible interactions between SNCA SNPs and environmental factors or disease progression is scarce. There is a need to expand the clinical applicability of these data as well as to investigate the role of SNCA SNPs in populations with different ethnic backgrounds.
| S-EPMC5525082 | biostudies-literature
Project description:Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder. Aging, environmental factors, and genetics are considered as risk factors. The alpha-synuclein gene (SNCA), the first pathogenic gene identified in a familial form of PD, was indisputably involved as a heritable component for familial and sporadic PD. In this study, whole-exome sequencing and Sanger sequencing were performed to evaluate the association between the SNCA gene variants and PD. The genetic data of 438 clinically diagnosed patients with PD and 543 matched control populations of the Han Chinese were analyzed. The literature review of SNCA variants for 231 cases reported in 89 articles was extracted from the PubMed and the Movement Disorder Society Genetic mutation database. No potentially causative variant(s) in the SNCA gene, excepting two single-nucleotide nonsynonymous variants c.158C>T (p.A53V, rs542171324) and c.349C>T (p.P117S, rs145138372), were detected. There was no statistically significant difference in the genotypic or allelic frequencies for either variant between the PD group and the control group (all P > 0.05). No copy number variants of the SNCA gene were detected. The results of this study suggest that the variants in the exons of the SNCA gene may have less or no role in the development of PD in the Han Chinese populations. The literature review suggests that psychiatric signs and cognitive decline/dementia were more common among patients with SNCA duplication or triplication (psychiatric signs: χ2 = 7.892, P = 0.005; cognitive decline/dementia: χ2 = 8.991, P = 0.003).
| S-EPMC8397385 | biostudies-literature
Project description:OBJECTIVE:Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. METHODS:We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. RESULTS:Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005). INTERPRETATION:Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.
| S-EPMC5221454 | biostudies-literature
Project description:The SNCA (Synuclein Alpha) gene represents a major risk gene for Parkinson's disease (PD) and SNCA polymorphisms have been associated with the common sporadic form of PD. Numerous Genome-Wide Association Studies showed strong signals located in the SNCA 3' UTR (untranslated region) region indicating that variants in 3' UTRs of PD-associated genes could contribute to neurodegeneration and may regulate the risk for PD. Genetic variants in 3' UTR can affect miRNA activity and consequently change the translation process. The aim of this study was to access the differences in 3' UTR variants of SNCA genes in a cohort of PD patients and control subjects from Croatia. The cohort consisted of 52 PD patients and 23 healthy control subjects. Differences between 3' UTR allele and genotype frequencies were accessed through next generation sequencing approach from whole blood samples. In our study, we identified four previously reported single nucleotide polymorphisms (SNPs) and one insertion in the 3' UTR region of SNCA gene, namely rs1045722, rs3857053, rs577490090, rs356165, and rs777296100, and five variants not reported in the literature, namely rs35270750, rs529553259, rs377356638, rs571454522, and rs750347645. Our results indicate a significantly higher occurrence of the rs571454522 variant in the PD population. To the best of our knowledge, this variant has not been reported until now in the literature. We analyzed our results in the context of previous research, creating a brief overview of the importance of 3' UTR variants of the SNCA gene. Further studies will be needed to gain a more profound insight regarding their role in PD development, which will help to assess the role and impact of post-transcriptional regulation on disease pathology.
| S-EPMC8698872 | biostudies-literature
Project description:BackgroundSNCA multiplication is a genomic cause of familial PD, showing dosage-dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case.ObjectivesWe have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole-genome sequencing data to elucidate the mechanism of SNCA duplication.MethodsSix patient samples with SNCA duplication underwent whole-genome sequencing. The duplicated regions were defined with nucleotide-resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non-B DNA-forming sequences and stem-loop structure predictions was conducted.ResultsDuplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2-4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem-loop structures.ConclusionOur study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem-loop structures suggest that replication-based rearrangements may be a common mechanism for SNCA amplification. © 2020 International Parkinson and Movement Disorder Society.
| S-EPMC7359376 | biostudies-literature
Project description:Background: Genetic factors have a well-known influence on Parkinson's disease (PD) susceptibility; however, no previous studies have investigated the influence of SNCA mutations on the natural history of PD using a prospective follow-up study. The aim of this study was to assess the risk factors of variation of SNCA on the prognosis symptoms of PD patients. Methods: Fifty PD patients were recruited with 38 v-PSG confirmed PD+RBD patients, and the median follow-up period was 30 months. All patients underwent a comprehensive clinical evaluation at baseline and follow-up, and six SNPs of SNCA (rs356165, rs3857053, rs1045722, rs894278, rs356186, and rs356219) were analyzed. Cox proportional hazards regression models and Kaplan-Meier plot analysis were used to assess the associations between the SNCA variation and the primary and secondary progression outcomes. Results: Based on the clinical assessment, we found that hyposmia was substantially easier to aggravate. Regression analysis showed that patients with the T allele of rs1045722 and the G allele of rs356219 presented a 34 and 20% decreased risk of progression to the H-Y stage, respectively (p = 0.022; p = 0.005). While for rs894278, G allele patients showed a 47% decreased risk of olfactory dysfunction (p = 0.029). Further subgroup analysis showed that PD+RBD patients with rs356219/G exhibited a 30% and 20% decreased risk of progression on the H-Y stage and MoCA score (p = 0.038; p = 0.045). Conclusions: Our results indicated that genetic variation in SNCA may contribute to variability natural progression of PD and could possibly be used as a prognostic marker.
| S-EPMC6562243 | biostudies-literature
Project description:Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Variants in the LRRK2 gene have been shown to be associated with PD. However, the clinical characteristics of LRRK2-related PD are heterogeneous. In our study, we performed a comprehensive pooled analysis of the association between specific LRRK2 variants and clinical features of PD. Methods: Articles from the Medline, Embase, and Cochrane databases were included in the meta-analysis. Strict inclusion criteria were applied, and detailed information was extracted from the final original articles included. Revman 5.3 software was used for publication biases and pooled and sensitivity analyses. Results: In all, 66 studies having the clinical manifestations of PD patients with G2019S, G2385R, R1628P, and R1441G were included for the final analysis. The prominent clinical features of LRRK2-G2019S-related PD patients were female sex, higher rates of early-onset PD (EOPD), and family history (OR: 0.77 [male], 1.37, 2.62; p < 0.00001, 0.02, < 0.00001). PD patients with G2019S were more likely to have high scores of Schwab & England (MD: 1.49; p < 0.00001), low GDS scores, high UPSIT scores (MD: 0.43, 4.70; p = 0.01, < 0.00001), and good response to L-dopa (OR: 2.33; p < 0.0001). Further, G2019S carriers had higher LEDD (MD: 115.20; p < 0.00001) and were more likely to develop motor complications, such as dyskinesia and motor fluctuations (OR: 2.18, 2.02; p < 0.00001, 0.04) than non-carriers. G2385R carriers were more likely to have family history (OR: 2.10; p = 0.007) than non-G2385R carriers and lower H-Y and higher MMSE scores (MD: -0.13, 1.02; p = 0.02, 0.0007). G2385R carriers had higher LEDD and tended to develop motor complications, such as motor fluctuations (MD: 53.22, OR: 3.17; p = 0.01, < 0.00001) than non-carriers. Other clinical presentations did not feature G2019S or G2385R. We observed no distinct clinical features for R1628P or R1441G. Our subgroup analyses in different ethnic group for specific variant also presented with relevant clinical characteristics of PD patients. Conclusions: Clinical heterogeneity was observed among LRRK2-associated PD in different variants in total and in different ethnic groups, especially for G2019S and G2385R.
| S-EPMC6156433 | biostudies-literature
Project description:The present study was to evaluate the diagnostic value of salivary total and oligomeric α-synuclein levels in PD. Furthermore, we sought to explore the relationship between salivary total α-synuclein and α-synuclein SNP variants levels. 201 PD patients and 67 controls were recruited, of which there also had the genetic information of two positive α-synuclein (SNCA) loci. Salivary total α-synuclein was assayed using a highly sensitive Luminex assay and oligomeric α-synuclein was quantified by the combination of Gel filtration chromatography and Western blot, respectively. From our analysis,No difference in salivary total α-synuclein levels was found between PD patients and healthy controls, it decreased with age in PD patients, and was closely associated with genotypic distribution of rs11931074 and rs894278 in PD, respectively. After controlled for age and genders, G allele of rs11931074 was correlated with lower salivary total α-synuclein levels, while G allele of rs894278 was also correlated with the higher levels. Simultaneously, the further study was shown that salivary oligomeric α-synuclein in PD patients significantly increased comparing to healthy controls. In conclusions,our study firstly demonstrated that salivary total α-synuclein levels could be manipulated by different α-synuclein SNPs and salivary oligomeric α-synuclein could be a potential diagnostic indicator of PD.
| S-EPMC4917865 | biostudies-literature
Project description:ObjectiveThe aim of this study was to systematically update the evidence for associations between host genetic variants and subgingival microbial detection and counts.Materials and methodsFollowing a previous systematic review (Nibali et al. J Clin Periodontol 43(11): 889-900, 15), an update of a systematic search of the literature was conducted in Ovid Medline, Embase, LILACS, and Cochrane Library for studies reporting data on host genetic variants and detection of microbes subgingivally published in the last 6 years.ResultsA total of 19 studies were included in the review, from an initial search of 2797 titles. Studies consisted mainly of candidate gene studies and of one genome-wide analysis. A total of 62 studies were considered for summary findings, including 43 identified in the previous systematic review of studies published up to 2015. Meta-analyses were done when appropriate including both papers in the original review and in the update. Meta-analyses revealed lack of associations between IL1 composite genotype and subgingival detection of Aggregatibacter acinomycetemcomitans, Poprhyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Prevotella intermedia. Promising evidence is emerging from other genetic variants and from sub-analyses of data from genome-association studies. Among other studies with candidate-gene, target SNPs were mainly within the IL10, IL6, IL4, IL8, IL17A, and VDR gene.ConclusionsIL1 composite genotype does not seem to be associated with subgingival microbial detection. Promising associations should be pursued by future studies, including studies employing -OMICS technologies.Clinical relevanceA better knowledge of which host genetic variant predispose to subgingival microbial colonization and to the development of progression of periodontal disease could potentially help to better understand periodontal disease pathogenesis and help with its management.
| S-EPMC8898234 | biostudies-literature
Project description:BackgroundPD is a progressive neurodegenerative disorder commonly treated by levodopa. The findings from genetic studies on adverse effects (ADRs) and levodopa efficacy are mostly inconclusive. Here, we aim to identify predictive genetic biomarkers for levodopa response (LR) and determine common molecular link with disease susceptibility. A systematic review for LR was conducted for ADR, and drug efficacy, independently. All included articles were assessed for methodological quality on 14 parameters. GWAS of PD were also reviewed. Protein-protein interaction (PPI) analysis using STRING and functional enrichment using WebGestalt was performed to explore the common link between LR and PD.ResultsFrom 37 candidate studies on levodopa toxicity, 18 genes were found associated, of which, CAn STR 13, 14 (DRD2) was most significantly associated with dyskinesia, followed by rs1801133 (MTHFR) with hyper-homocysteinemia, and rs474559 (HOMER1) with hallucination. Similarly, 8 studies on efficacy resulted in 4 genes in which rs28363170, rs3836790 (SLC6A3) and rs4680 (COMT), were significant. To establish the molecular connection between LR with PD, we identified 35 genes significantly associated with PD. With 19 proteins associated with LR and 35 with PD, two independent PPI networks were constructed. Among the 67 nodes (263 edges) in LR, and 62 nodes (190 edges) in PD pathophysiology, UBC, SNCA, FYN, SRC, CAMK2A, and SLC6A3 were identified as common potential candidates.ConclusionOur study revealed the genetically significant polymorphism concerning the ADRs and levodopa efficacy. The six common genes may be used as predictive markers for therapy optimization and as putative drug target candidates.
| S-EPMC5606117 | biostudies-literature