Lack of evidence for genetic association of saposins A, B, C and D with Parkinson's disease.
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ABSTRACT:
SUBMITTER: Sosero YL
PROVIDER: S-EPMC7523699 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations. METHODS: Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland. RESULTS: No association was found in any of the populations studied. CONCLUSION: Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations.
| S-EPMC1183215 | biostudies-literature
Project description:UCHL1 has been proposed as a candidate gene for Parkinson's disease (PD). A meta-analysis of white and Asian subjects reported an inverse association between the non-synonymous UCHL1 S18Y polymorphism and PD risk. However, this finding was not replicated in a large case-control study and updated meta-analysis restricted to white subjects. We performed a case-control study of 1757 PD patients recruited from movement disorder clinics and 2016 unrelated controls from four regions of the United States. All subjects self-reported as white. We did not observe evidence for an association between S18Y genotypes and PD (overall P-value for association: P = 0.42). After adjustment for age, sex, and recruitment region, the odds ratio for Y/S versus S/S was 0.91 (95% CI: 0.78-1.06) and for Y/Y versus S/S was 0.87 (95% CI: 0.58-1.29). We also did not observe a significant association for recessive or dominant models of inheritance, or after stratification by age at onset, age at blood draw, sex, family history of PD, or recruitment region. Our results suggest that UCHL1 S18Y is not a major susceptibility factor for PD in white populations although we cannot exclude the possibility that the S18Y variant exerts weak effects on risk, particularly in early-onset disease.
| S-EPMC2823263 | biostudies-literature
Project description:Background:The phospholipase A2 Group 6 (PLA2G6, also known as PLA2, PARK14, and iPLA2) gene encodes a group VIA calcium-independent phospholipase A2. Genetic polymorphism of PLA2G6 has been indicated to be involved in conferring susceptibility for Parkinson's disease (PD), whereas conclusive results have not been obtained. Thus, we intended to conduct a systematic review to determine if PLA2G6 genetic variation confers a greater susceptibility to PD. Methods:All case-control studies that investigated the association of the PLA2G6 polymorphisms with the risk of PD published before 15 July 2018 were included. The literature was comprehensively searched and identified in five English databases (EBSCO, Pubmed, OVID, EMBASE and ISI Web of Knowledge) and four Chinese databases (Wanfang database, Chinese Biomedical Literature Database, China Academic Journals Database and VIP database). We performed analyses of study characteristics, heterogeneity, and forest plot in analyses analogous to dominant, codominant and additive models with the pooled odds ratio (OR) in fixed- or random-effects models as the measure of association. Results:A total of 664 potentially relevant studies were retrieved with the initial search, of which eight studies fulfilled the inclusion criteria, and included 2,779 PD patients and 3,291 control participants,. Among all the reported 27 genetic variants, 15 single nucleotide polymorphisms (SNPs) were present only in patients, and only five available SNPs (rs2267369, rs140758033, c.1959T>A (Gly653Gly), rs76718524, rs199935023) were pooled in the meta-analysis. However, there was no evidence for a significant association between the five SNPs and PD risk in dominant, codominant and allele models, suggesting a lack of association between PLA2G6 genetic variation and PD susceptibility. Conclusion:The present study assessed the association of PLA2G6 genetic polymorphism with the risk PD, and the result strongly demonstrates that PLA2G6 polymorphism is not associated with PD susceptibility.
| S-EPMC7399463 | biostudies-literature
Project description:Parkin (PRKN) mutations are a common cause of early-onset parkinsonism, however the role of this gene in typical late-onset Parkinson's disease (PD) remains unresolved. A single nucleotide polymorphism in the promoter region (PRKN-258; rs9347683) has been observed to associate with PD, affect age-at-onset (AAO) of symptoms, and to functionally effect differential expression of the PRKN transcript. In the present study, PRKN-258 did not associate with PD, and no evidence for an AAO effect was observed in three age and gender-matched Caucasian patient-control series from Norway, Ireland and the US. These data do not support a role for this common variant in PD etiology.
| S-EPMC4381345 | biostudies-literature
Project description:Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.
| S-EPMC5812479 | biostudies-literature
Project description:BACKGROUND AND AIMS:Similar clinical and pathological features have been observed in Alzheimer's disease (AD) and Parkinson's disease with dementia (PDD). Both the peroxisome proliferator-activated receptor-? (PPAR-?) gene and the peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) gene are candidates modifying the risk for both diseases. The aim of this study was to clarify whether common single nucleotide polymorphisms (SNPs) of the PPAR-? gene and the PGC-1? gene affect the onset of AD and PDD genetically. METHODS:Four exonic SNPs of both genes (rs1801282 and rs3856806 of the PPAR-? gene, rs3736265 and rs8192678 of the PGC-1? gene) were genotyped in 171 AD patients, 136 age-matched controls and 53 PDD patients. Haplotype analysis and logistic regression analysis with apolipoprotein E (APO E) status were performed for AD. RESULTS:There was no statistical difference between AD cases and controls for the 4 SNPs, nor was there any statistical difference between PDD cases and controls for the 4 SNPs. We could not find any synergetic associations between these SNPs, APO E4 and AD. CONCLUSIONS:The 4 SNPs studied here did not influence the risk for AD in a Japanese population. As the number of PDD cases was small, comprehensive genetic studies considering diabetes would be needed.
| S-EPMC3670632 | biostudies-literature
Project description:Low DJ-1 protein level caused by DJ-1 gene mutation leads to autosomal recessive Parkinson's disease (PD) due to impaired antioxidative activity. In sporadic PD patients, although mutations were rarely found, lower DJ-1 protein level was also reported. Dysregulation of DJ-1 gene expression might contribute to low DJ-1 protein level. Since the promoter is the most important element to initiate gene expression, whether polymorphisms in the DJ-1 promoter result in the dysregulation of gene expression, thus leading to low protein level and causing PD, is worth exploring. The DJ-1 promoter region was sequenced in a Chinese cohort to evaluate possible links between DJ-1 promoter polymorphisms, PD risk and clinical phenotypes. Dual-luciferase reporter assay was conducted to evaluate the influence of promoter polymorphisms on DJ-1 transcriptional activity. Related information in an existing genome-wide association studies (GWAS) database were looked up, meta-analysis of the present study and other previous reports was conducted, and expression quantitative trait loci (eQTL) analysis was performed to further explore the association. Three single nucleotide polymorphisms (SNPs) (rs17523802, rs226249, and rs35675666) and one 18 bp deletion (rs200968609) were observed in our cohort. However, there was no significant association between the four detected genetic variations and the risk of PD either in allelic or genotype model, in single-point analysis or haplotype analysis. This was supported by the meta-analysis of this study and previous reports as well as that of GWAS database PDGene. Dual luciferase reporter assay suggested these promoter polymorphisms had no influence on DJ-1 transcriptive activity, which is consistent with the eQTL analysis results using the data from GTEx database. Thus, DJ-1 promoter polymorphisms may play little role in the dysregulation of DJ-1 expression and PD susceptibility in sporadic PD.
| S-EPMC6399152 | biostudies-literature
Project description:Post-mortem Lewy body and Lewy neuritic inclusions are a defining feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). With the discovery of missense and multiplication mutations in the alpha-synuclein gene (SNCA) in familial parkinsonism, Lewy inclusions were found to stain intensely with antibodies raised against the protein. Yeast-two-hybrid studies identified synphilin-1 as an interacting partner of alpha-synuclein, and both proteins show co-immunolocalization in a subset of Lewy body inclusions. In the present study, we have investigated whether common variability in synphilin-1, including coding substitutions are genetically associated with disease pathogenesis.We screened the synphilin-1 gene for 11 single nucleotide polymorphisms (SNPs) in 300 affected subjects with idiopathic Parkinson's disease and 412 healthy controls. Six of these were rare variants including five previously identified amino acid substitutions that were chosen in a direct approach for association of rare disease causing mutations. An additional five highly heterozygous SNPs were chosen for an indirect association approach including haplotype analysis, based on the assumption that any disease causing mutations might be in linkage disequilibrium with the SNPs selected. We also genotyped a microsatellite marker (D5S2950) within intron 6 of the gene and five additional microsatellites clustered downstream of the 5p23.1-23.3 synphilin-1 locus. Genome-wide linkage analysis, in a number of independent studies, has previously highlighted suggestive linkage to PD in this region of chromosome 5.Screening of previously known amino acid substitutions in the synphilin-1 gene, identified the C1861>T (R621C) substitution in four patients (chromosomes n = 600) and 10 control subjects (chromosomes n = 824), whereas the G2125>C (E706Q) substitution was detected in one patient and four control subject, suggesting both these substitutions are not associated with susceptibility to PD. Heterozygous non-synonymous T131>C (V44A) and synonymous C636>T (P212P) amino acid substitutions were each detected in only one patient with PD. Heterozygous C1134>T (L378L) synonymous substitutions were found in two patients with PD and one control subject. D5S2010 the most distal telomeric microsatellite marker genotyped,15.3 Mb from synphilin-1, was genetically associated with PD (p = 0.006, 27df) independently adjusted for multiple testing according to its high amount of alleles but not the total number of other markers investigated. Other flanking and intronic SNP and microsatellite markers showed no evidence for genetic association with disease.In this study rare synphilin-1 SNPs were assessed in a direct association approach to identify amino acid substitutions that might confer risk of PD in a homozygous or compound heterozygous state. We found none of these rare variations were associated with disease. In contrast to prior studies the frequency of the R621C substitution was not significantly different between PD and control subjects, neither were the V44A or E706Q substitutions. Similarly, our indirect study of more heterozygous SNPs, including both single marker and haplotype analyses, showed no significant association to PD. However, marginal association of microsatellite alleles with idiopathic PD, within the chromosome 5q21 region, indicates further studies are warranted.
| S-EPMC2329608 | biostudies-literature
Project description:We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding alpha-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
| S-EPMC2787725 | biostudies-literature
Project description:BackgroundMotor complications are a consequence of the chronic dopaminergic treatment of Parkinson's disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population.ObjectiveTo evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD.MethodsMotor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models.ResultsIn 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43).ConclusionThis study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD.
| S-EPMC8609705 | biostudies-literature