The Relationship between Alpha-Synuclein (SNCA) Gene Polymorphisms and Development Risk of Parkinson’s Disease (original) (raw)

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.

Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease

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.

Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease

Neuroscience Letters, 2005

It remains unclear whether genetic variants in SNCA (the alpha-synuclein gene) alter risk for sporadic Parkinson's disease (PD). The polymorphic mixed sequence repeat (NACP-Rep1) in the promoter region of SNCA has been previously examined as a potential susceptibility factor for PD with conflicting results. We report genotype and allele distributions at this locus from 369 PD cases and 370 control subjects of European Australian ancestry, with alleles designated as −1, 0, +1, +2, and +3 as previously described. Allele frequencies designated (0) were less common in Australian cases compared to controls (OR = 0.80, 95% CI 0.62-1.03). Combined analysis including all previously published ancestral European Rep1 data yielded a highly significant association between the 0 allele and a reduced risk for PD (OR = 0.79, 95% CI 0.70-0.89, p = 0.0001). Further study must now proceed to examine in detail this interesting and biologically plausible genetic association.

-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.

Multiple candidate gene analysis identifies -synuclein as a susceptibility gene for sporadic Parkinson's disease

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.

Alpha-synuclein polymorphisms are associated with Parkinson's disease in a Saskatchewan population

Movement Disorders, 2009

A clinical overlap between Parkinson's disease (PD) and essential tremor (ET) has prompted a discussion whether these conditions share common genetic susceptibility factors. Recently, the first genome-wide association study in ET revealed a significant association with a variant in the LINGO1 gene. LINGO1 has also been demonstrated to play a role in the survival of dopaminergic neurons in an animal model of PD, and therefore constitutes a potential candidate gene for PD. In this study, SNPs rs9652490, rs11856808, and rs7177008 of LINGO1 were genotyped in a total of 694 Austrian subjects (349 PD, 345 controls). No association could be found between genotype or allele counts and PD. Neither did a subgroup analysis in tremor-dominant patients with PD reveal a significant association. This study on LINGO1-variants in PD argues against a major role of LINGO1 gene variations for PD.

SNCA Variant Associated With Parkinson Disease and Plasma α-Synuclein Level

Archives of Neurology, 2010

Objective-A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson's disease (PD). There is also increasing evidence that SNPs elsewhere in the gene associate with risk. We sought to further explore the disease association, determine whether evidence of allelic heterogeneity exists, and examine the correlation between PDassociated variants and plasma α-synuclein levels.