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Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

Al-Chalabi A, Dürr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, Leigh PN, Bensimon G, NNIPPS Genetic Study Gro - PLoS ONE (2009)

Bottom Line: A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)).The association with rs3822086 was replicated in the independent samples (P = 0.035).The strongest association is with the cerebellar subtype of MSA.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, and NIHR Biomedical Research Centre, London, United Kingdom. ammar@iop.kcl.ac.uk

ABSTRACT

Background: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA.

Methodology/findings: We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035).

Conclusions/significance: We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.

Trial registration: ClinicalTrials.gov NCT00211224.

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Related in: MedlinePlus

The genetic architecture of the SNCA gene and the markers genotyped.The base pair position along chromosome 4 is shown by the top ruler. The position of the α-synuclein gene is shown in the next row down, with exons represented by vertical lines and introns by lines connecting them. The relative positions of the genotyped markers are shown below, with vertical lines connecting position to the linkage disequilibrium map. Asterisks show the two markers demonstrating association in MSA-C. Only the left-most marker showed association with MSA as a whole. (For a list of markers genotyped and P-values, see Table 3). The coloured triangle is the linkage disequilibrium heat map showing the strength of association between pairs of markers as measured by D′. Red is high and blue low with the other colours intermediate. The two associated SNPs are in different linkage disequilibrium blocks and are not in linkage disequilibrium with each other.
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pone-0007114-g001: The genetic architecture of the SNCA gene and the markers genotyped.The base pair position along chromosome 4 is shown by the top ruler. The position of the α-synuclein gene is shown in the next row down, with exons represented by vertical lines and introns by lines connecting them. The relative positions of the genotyped markers are shown below, with vertical lines connecting position to the linkage disequilibrium map. Asterisks show the two markers demonstrating association in MSA-C. Only the left-most marker showed association with MSA as a whole. (For a list of markers genotyped and P-values, see Table 3). The coloured triangle is the linkage disequilibrium heat map showing the strength of association between pairs of markers as measured by D′. Red is high and blue low with the other colours intermediate. The two associated SNPs are in different linkage disequilibrium blocks and are not in linkage disequilibrium with each other.

Mentions: 32 SNPs in and around SNCA were selected for association testing with MSA (Figure 1, Table 3). In addition, we genotyped the multi-allelic microsatellite repeat known as NACP-Rep1 which is situated within the promoter region ∼10 kbp upstream of the translational start point of SNCA at chromosome 4q21, using an ABI3130XL Genotyper (Applied Biosystems) and Genotyper v4.0 software. This complex microsatellite with sequence (TC)10–11TT(TC)8–11(TA)7–9(CA)10–11 has been variably associated with PD [22], [23] but not MSA [12], although the numbers studied were small. There are five common alleles, each differing in size by two nucleotides, the greatest variability being in the CA portion with subsidiary variability in the (TC)8–11(TA)7–9 portion. However, ex vivo functional analysis suggests that the overall length of the microsatellite rather than its sequence, determines transcriptional regulation and hence SNCA gene expression [24]. We numbered the alleles from 1 to 5 in order of increasing size.


Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

Al-Chalabi A, Dürr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, Leigh PN, Bensimon G, NNIPPS Genetic Study Gro - PLoS ONE (2009)

The genetic architecture of the SNCA gene and the markers genotyped.The base pair position along chromosome 4 is shown by the top ruler. The position of the α-synuclein gene is shown in the next row down, with exons represented by vertical lines and introns by lines connecting them. The relative positions of the genotyped markers are shown below, with vertical lines connecting position to the linkage disequilibrium map. Asterisks show the two markers demonstrating association in MSA-C. Only the left-most marker showed association with MSA as a whole. (For a list of markers genotyped and P-values, see Table 3). The coloured triangle is the linkage disequilibrium heat map showing the strength of association between pairs of markers as measured by D′. Red is high and blue low with the other colours intermediate. The two associated SNPs are in different linkage disequilibrium blocks and are not in linkage disequilibrium with each other.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2743996&req=5

pone-0007114-g001: The genetic architecture of the SNCA gene and the markers genotyped.The base pair position along chromosome 4 is shown by the top ruler. The position of the α-synuclein gene is shown in the next row down, with exons represented by vertical lines and introns by lines connecting them. The relative positions of the genotyped markers are shown below, with vertical lines connecting position to the linkage disequilibrium map. Asterisks show the two markers demonstrating association in MSA-C. Only the left-most marker showed association with MSA as a whole. (For a list of markers genotyped and P-values, see Table 3). The coloured triangle is the linkage disequilibrium heat map showing the strength of association between pairs of markers as measured by D′. Red is high and blue low with the other colours intermediate. The two associated SNPs are in different linkage disequilibrium blocks and are not in linkage disequilibrium with each other.
Mentions: 32 SNPs in and around SNCA were selected for association testing with MSA (Figure 1, Table 3). In addition, we genotyped the multi-allelic microsatellite repeat known as NACP-Rep1 which is situated within the promoter region ∼10 kbp upstream of the translational start point of SNCA at chromosome 4q21, using an ABI3130XL Genotyper (Applied Biosystems) and Genotyper v4.0 software. This complex microsatellite with sequence (TC)10–11TT(TC)8–11(TA)7–9(CA)10–11 has been variably associated with PD [22], [23] but not MSA [12], although the numbers studied were small. There are five common alleles, each differing in size by two nucleotides, the greatest variability being in the CA portion with subsidiary variability in the (TC)8–11(TA)7–9 portion. However, ex vivo functional analysis suggests that the overall length of the microsatellite rather than its sequence, determines transcriptional regulation and hence SNCA gene expression [24]. We numbered the alleles from 1 to 5 in order of increasing size.

Bottom Line: A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)).The association with rs3822086 was replicated in the independent samples (P = 0.035).The strongest association is with the cerebellar subtype of MSA.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, and NIHR Biomedical Research Centre, London, United Kingdom. ammar@iop.kcl.ac.uk

ABSTRACT

Background: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA.

Methodology/findings: We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035).

Conclusions/significance: We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.

Trial registration: ClinicalTrials.gov NCT00211224.

Show MeSH
Related in: MedlinePlus