Alpha-synuclein transcript isoforms in three different brain regions from Parkinson's disease and healthy subjects in relation to the SNCA rs356165/rs11931074 polymorphisms (original) (raw)
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Genetic association between α-synuclein and idiopathic parkinson's disease
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008
Point mutations and copy number variations in SNCA, the gene encoding a-synuclein, cause familial Parkinson's disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) ¼ 0.86, P ¼ 0.006 for 257-carriers; OR ¼ 1.25, P ¼ 0.022 for 261-carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P ¼ 0.002 in overall data, 0.003 in non-familial PD, 0.001 in early-onset PD; for 261, P ¼ 0.056 in overall data, 0.024 in non-familial PD, 0.052 in early-onset PD). The 257associated risk was consistent with a dominant model [hazard ratio (HR) ¼ 0.99, P ¼ 0.91 for 257/ 257 vs. 257/X where X denotes all other common alleles; HR ¼ 1.16, P ¼ 0.004 for X/X vs. 257/X]. The 261-associated risk was consistent with a recessive model (HR ¼ 1.89, P ¼ 0.026 for 261/261 vs. 261/X; HR ¼ 0.95, P ¼ 0.42 for X/X vs. 261/X). Genotypespecific mean onset ages (AESD) ranged from 54.8 AE 12.1 for 261/261 to 59.4 AE 11.5 for 257/ 257, displaying a trend of decreasing onset age with increasing allele size (P ¼ 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD.
Human Molecular Genetics, 2006
Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case-control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case-control populations, we found that a SNP in a-synuclein (SNCA), rs7684318, showed the strongest association with PD (P 5 5.0 3 10 210). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D 0 > 0.9) spanning 120 kb. A tight LD group (r 2 > 0.85) of six SNPs, including rs7684318, associated most strongly with PD (P 5 2.0 3 10 29-1.7 3 10 211). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.
Human Molecular Genetics, 2006
Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case -control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case -control populations, we found that a SNP in a-synuclein (SNCA), rs7684318, showed the strongest association with PD (P 5 5.0 3 10 210 ). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D 0 > 0.9) spanning 120 kb. A tight LD group (r 2 > 0.85) of six SNPs, including rs7684318, associated most strongly with PD (P 5 2.0 3 10 29 -1.7 3 10 211 ). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.
-Synuclein and Parkinson disease susceptibility
Neurology, 2007
Background: Mutations in the ␣-synuclein (SNCA) gene have been shown to be responsible for a rare familial form of Parkinson disease (PD). Furthermore, polymorphic variants in multiple regions of the gene have been associated with susceptibility to idiopathic PD in different populations.
Journal of neural transmission (Vienna, Austria : 1996), 2003
Mutations of the alpha-synuclein gene have shown to be relevant in some rare families with autosomal dominant Parkinson's disease (PD). Furthermore, alpha-synuclein protein is a major component of the Lewy bodies also in sporadic PD patients. Increased levels of wildtype alpha-synuclein in the cell leads to increased intracellular hydrogen peroxide levels and causes death of dopaminergic neurons in rat primary culture. Subsequently, oxidative stress has been directly linked with alpha-synuclein aggregation in vitro. This raises the question whether increased alpha-synuclein expression might be linked to higher susceptibility to PD and whether alpha-synuclein promoter polymorphisms are associated with PD. Here, two polymorphisms (-116C>G and -668T>C) of the alpha-synuclein promoter defining four haplotypes have been characterized in 315 German PD patients. The influence of the four haplotypes on gene expression was studied by CAT reporter gene assays in neuronal SK-N-AS cel...
Beta-synuclein gene variants and Parkinson's disease: A preliminary case-control study
Neuroscience Letters, 2007
Aggregation and fibrillization of the alpha-synuclein protein, which is the main component of Lewy bodies, may represent important processes in the pathogenesis of Parkinson's disease (PD). Several in vivo and in vitro studies suggest that beta-synuclein may be a natural negative regulator of alphasynuclein aggregation and fibrillization. The goal of the present study was to investigate the association of two polymorphisms (rs35035889 and rs1352303) in the beta-synuclein (SNCB) gene with PD. Our case-control study included a total of 370 case-unaffected sibling pairs and 168 caseunrelated control pairs (538 pairs total). The subjects were recruited from an ongoing study of the molecular epidemiology of PD in the Upper Midwest (USA). We employed a liberalization of the sibling transmission disequilibrium test to study the main effects of the gene variants for subjects overall and for strata defined by age at study, gender, ethnicity, clinical diagnostic certainty, dementia, and family history of PD (adjusted for age at study and gender as appropriate). The analyses were conducted for each SNCB variant separately, and also for two-locus haplotypes using score tests. Neither of the SNCB SNPs examined were associated with PD overall or in strata, and haplotype analyses were negative as well. However, one of the two SNPs (rs1352303) was associated with a delayed age at onset of PD in women. The results of this preliminary study suggest that the SNCB locus, though not a susceptibility gene for PD, might modify the age at onset of PD. Genotype n (%) Dominant Model a Sample or Stratum b n 1/1 1/2 2/2 OR (95% CI) p-value Cases, all 538 151 (28.1) 258 (48.0) 129 (24.0) 0.98 (0.70-1.36) 0.89 Controls, all 538 147 (27.3) 262 (48.7) 129 (24.0) Cases, women 197 48 (24.4) 99 (50.3) 50 (25.4) 1.09 (0.66-1.81) 0.73 Controls, women 197 51 (24.4) 93 (47.2) 53 (26.9) Cases, men 205 61 (29.8) 96 (46.8) 48 (23.4)
Movement Disorders, 2006
␣-Synuclein is one of the main components of Lewy bodies, a pathological marker of Parkinson's disease (PD). Certain missense mutations of the ␣-synuclein gene cause familial PD, but the role of the gene in sporadic PD is still controversial. We scrutinized polymorphisms of the ␣-synuclein gene in a Japanese population and investigated their associations with sporadic cases of PD. The 5Ј flanking region to intron 2 of the ␣-synuclein gene (3.8 kb) and two polymorphisms in intron 4 previously reported in Caucasian sporadic cases of PD were analyzed in 185 sporadic PD and 191 controls. Five novel single nucleotide polymorphisms (SNPs), 16 reported SNPs, and one reported polynucleotide polymorphism (PNP) were found. Most of the polymorphisms examined were in linkage disequilibrium. Significant associations with PD were found in 15 of 21 SNPs, especially in intron 1 (IVS1ϩ155 TmAn PNP and the IVS1ϩ719 CϾT SNP, P Ͻ 0.0001). Haplotype analysis showed that T10A7-A-A and T11A6-G-G haplotypes at three loci (IVS1ϩ155 -IVS1ϩ273 -IVS1ϩ608) were strongly negative and positive risk factors of sporadic PD, respectively (odds ratios were 0.23 [95% confidence interval, 0.16 -0.32] and 1.51 [95% confidence interval, 1.29 -1.75]). In conclusion, our findings indicate that genetic variations of the ␣-synuclein gene affect the development of sporadic PD.
Alpha-synuclein and familial Parkinson's disease
Movement Disorders, 2009
Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3′ region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3′ region of SNCA. The four SNPs were in high LD (r 2 > 0.95) and were analyzed as a haplotype.