Genetic Variants of the α-Synuclein Gene SNCA Are Associated with Multiple System Atrophy

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 α-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the α-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 = 8.7×10−4). The association with rs3822086 was replicated in the independent samples (P = 0.035). Conclusions/Significance We report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. Trial Registration ClinicalTrials.gov NCT00211224. [NCT00211224]

• Publication year

  2009

• Venue

  PLoS ONE

• Publication date

  2009-09-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0007114PMID 19771175PMCID 2743996
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• SNCA variants are associated with increased risk for multiple system atrophy

  2009influential reference
• Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 Genes

  2008cited by this paper
• Second consensus statement on the diagnosis of multiple system atrophy

  2008influential reference
• Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study

  2008influential reference
• PLINK: a tool set for whole-genome association and population-based linkage analyses.

  2007cited by this paper
• A new multipoint method for genome-wide association studies by imputation of genotypes

  2007influential reference
• Multiplex families with multiple system atrophy.

  2007cited by this paper
• Heredity in multiple system atrophy.

  2006cited by this paper
• The α-synuclein gene in multiple system atrophy

  2006cited by this paper
• MSA-C is the predominant clinical phenotype of MSA in Japan: analysis of 142 patients with probable MSA.

  2006cited by this paper
• Alpha-1-antichymotrypsin gene polymorphism and susceptibility to multiple system atrophy (MSA).

  2005cited by this paper
• Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease.

  2005cited by this paper
• Brain‐derived neurotrophic factor gene polymorphisms in Japanese patients with sporadic Alzheimer's disease, Parkinson's disease, and multiple system atrophy

  2005cited by this paper
• Interleukin-8, intercellular adhesion molecule-1 and tumour necrosis factor-alpha gene polymorphisms and the risk for multiple system atrophy.

  2005cited by this paper
• Probable multiple system atrophy in a German family

  2004cited by this paper
• alpha-Synuclein promoter confers susceptibility to Parkinson's disease.

  2004cited by this paper
• α‐Synuclein promoter confers susceptibility to Parkinson's disease

  2004cited by this paper
• Variations in the dopamine beta-hydroxylase gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy.

  2003cited by this paper
• Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene.

  2003cited by this paper
• Functional analysis of intra-allelic variation at NACP-Rep1 in the α-synuclein gene

  2003cited by this paper
• Interleukin‐1A (−889) genetic polymorphism increases the risk of multiple system atrophy

  2003cited by this paper
• Variations in the dopamine β‐hydroxylase gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy

  2003cited by this paper
• Contribution of the interleukin‐1β gene polymorphism in multiple system atrophy

  2002cited by this paper
• Contribution of the interleukin-1beta gene polymorphism in multiple system atrophy.

  2002cited by this paper
• Multiple system atrophy/progressive supranuclear palsy: α-Synuclein, synphilin, tau, and APOE

  2000cited by this paper
• No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy.

  1999cited by this paper
• Apolipoprotein E e4 allele frequency in patients with multiple system atrophy.

  1997cited by this paper
• CYP2D6‐debrisoquine hydroxylase gene polymorphism in multiple system atrophy

  1995cited by this paper
• [Oligodendroglial inclusions, a marker of multisystemic atrophies].

  1992cited by this paper
• Oligodendroglial Microtubular Tangles in Olivopontocerebellar Atrophy

  1990cited by this paper
• FAMILIAL ORTHOSTATIC HYPOTENSION.

  1964cited by this paper

• Alpha-Synuclein in Neurodegeneration: From Shared Biology to Disease-Specific Phenotypes

  2026cites this paper
• When Proteins Go MAD—Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection

  2026cites this paper
• Phase 1, randomized trials of MEDI1341: cerebrospinal fluid free α-synuclein lowered by >50%

  2025cites this paper
• Multiple system atrophy: advances in pathogenesis and emerging therapeutic strategies

  2025cites this paper
• Parkinson’s Spectrum Mechanisms in Pregnancy: Exploring Hypothetical Scenarios for MSA in the Era of ART

  2025cites this paper
• Common SNCA Genetic Variants and Parkinson’s Disease Risk: A Systematic Review and Meta-Analysis

  2025cites this paper
• Integrative Analysis of Metabolome and Proteome in the Cerebrospinal Fluid of Patients with Multiple System Atrophy

  2025cites this paper
• Molecular mechanisms of exercise-induced neuroprotection against Parkinson's disease.

  2025cites this paper
• Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies

  2024cites this paper
• Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials

  2024cites this paper
• Genome sequence analyses identify novel risk loci for multiple system atrophy.

  2024cites this paper
• Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy.

  2023cites this paper
• The genetic basis of multiple system atrophy

  2023cites this paper
• Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

  2023cites this paper
• COQ2 and SNCA polymorphisms interact with environmental factors to modulate the risk of multiple system atrophy and subtype disposition

  2022cites this paper
• Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad

  2022cites this paper
• The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches.

  2022cites this paper
• A historical review of multiple system atrophy with a critical appraisal of cellular and animal models

  2021cites this paper
• Current experimental disease-modifying therapeutics for multiple system atrophy

  2021cites this paper
• Multiple System Atrophy (MSA)

  2021cites this paper
• Antisense Oligonucleotide Therapeutics for Neurodegenerative Disorders

  2021cites this paper
• Frequency of spinocerebellar ataxia mutations in patients with multiple system atrophy

  2021cites this paper
• Multiple System Atrophy

  2021cites this paper
• The Genetic Landscape of Parkinsonism-Related Dystonias and Atypical Parkinsonism-Related Syndromes

  2021cites this paper
• Multiple system atrophy and C9orf72 hexanucleotide repeat expansions in a cohort of Italian patients.

  2021cites this paper
• Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system

  2021cites this paper
• Genetics of synucleins in neurodegenerative diseases

  2020cites this paper
• Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

  2020cites this paper
• Plant community and phylogenetic shifts in acid seep springs over 49 years following Microstegium vimineum invasion

  2020cites this paper
• Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis

  2020cites this paper
• Mini-Review: The MSA transcriptome

  2020cites this paper
• Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy

  2020cites this paper
• Mechanisms of alpha-synuclein toxicity: An update and outlook.

  2020cites this paper
• Role of Genes and Treatments for Parkinson’s Disease

  2020cites this paper
• Multiple system atrophy - a clinicopathological update.

  2020cites this paper
• The cis-Regulatory Element of SNCA Intron 4 Modulates Susceptibility to Parkinson’s Disease in Han Chinese

  2020cites this paper
• Multiple system atrophy.

  2019cites this paper
• Genetics of REM Sleep Behavior Disorder

  2019cites this paper
• MicroRNAs Dysregulation and Metabolism in Multiple System Atrophy

  2019cites this paper
• Modeling α-Synuclein Propagation with Preformed Fibril Injections

  2019cites this paper
• Cross-examining candidate genes implicated in multiple system atrophy

  2019cites this paper
• Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update—I. Hypokinetic-rigid movement disorders

  2019cites this paper
• Selection signatures in four German warmblood horse breeds: Tracing breeding history in the modern sport horse

  2019cites this paper
• Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson’s disease

  2019cites this paper
• In vitro models of multiple system atrophy from primary cells to induced pluripotent stem cells

  2018cites this paper
• Direct effects of warming increase woody plant abundance in a subarctic wetland

  2018cites this paper
• Lysosomal storage disorder gene variants in multiple system atrophy.

  2018cites this paper
• Tryptophan 32-mediated SOD1 aggregation is attenuated by pyrimidine-like compounds in living cells

  2018cites this paper
• The impact of the Inca Empire in Northwest Argentina: Assessment of health status and food consumption at Esquina de Huajra (Quebrada de Humahuaca, Argentina)

  2018cites this paper
• Association analysis of SNP rs11868035 in SREBF1 with sporadic Parkinson's disease, sporadic amyotrophic lateral sclerosis and multiple system atrophy in a Chinese population.

  2018cites this paper
• Disorders with Synuclein Pathology and P arkinsonism

  2018cites this paper
• α-Synuclein: Multiple System Atrophy Prions.

  2018cites this paper
• Limited effects of dysfunctional macroautophagy on the accumulation of extracellularly derived α-synuclein in oligodendroglia: implications for MSA pathogenesis

  2018cites this paper
• The prion-like properties of assembled human alpha-synuclein

  2018cites this paper
• The Use of Co-immunoprecipitation to Study Conformation-Specific Protein Interactions of Oligomeric α-Synuclein Aggregates

  2018cites this paper
• Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants.

  2018cites this paper
• Responses of rat and mouse primary microglia to pro- and anti-inflammatory stimuli: molecular profiles, K+ channels and migration

  2017cites this paper
• Key themes and future prospects in translational multiple system atrophy research.

  2017cites this paper
• Multiple System Atrophy: Clinical, Genetics, and Neuropathology

  2017cites this paper
• The Synucleinopathies: Twenty Years On

  2017cites this paper
• Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy

  2017cites this paper
• Neurodegeneration and the ordered assembly of α-synuclein

  2017cites this paper
• Potential effects of low molecular weight phthalate esters (C16H22O4 and C12H14O4) on the freshwater fish Cyprinus carpio.

  2017cites this paper
• Multiple system atrophy: insights into a rare and debilitating movement disorder

  2017cites this paper
• Multiple system atrophy: experimental models and reality

  2017cites this paper
• Real‐time cell analysis and heat shock protein gene expression in the TcA Tribolium castaneum cell line in response to environmental stress conditions

  2017cites this paper
• Structural variants in SNCA gene and the implication to synucleinopathies.

  2017cites this paper
• Multiple system atrophy: genetic risks and alpha-synuclein mutations

  2017cites this paper
• Discovering the 3′ UTR-mediated regulation of alpha-synuclein

  2017cites this paper
• Protein Aggregation and Neurodegeneration: Tauopathies and Synucleinopathies

  2017cites this paper
• Atypical parkinsonism - new advances.

  2016cites this paper
• Animal modeling an oligodendrogliopathy – multiple system atrophy

  2016cites this paper
• Revista Española de Geriatría y Gerontología

  2016cites this paper
• Review: Multiple system atrophy: emerging targets for interventional therapies

  2016cites this paper
• Glia and alpha-synuclein in neurodegeneration: A complex interaction.

  2016cites this paper
• Coenzyme Q10 Levels Are Decreased in the Cerebellum of Multiple-System Atrophy Patients

  2016cites this paper
• A genome-wide association study in multiple system atrophy

  2016cites this paper
• Active immunization therapies for Parkinson's disease and multiple system atrophy

  2016cites this paper
• A novel mathematical model of ATM/p53/NF- κB pathways points to the importance of the DDR switch-off mechanisms

  2016cites this paper
• Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

  2016cites this paper
• Up-regulation of SNCA gene expression: implications to synucleinopathies

  2016cites this paper
• Strand-specific RNA-sequencing analysis of multiple system atrophy brain transcriptome.

  2016cites this paper
• Chapter 58 – Animal Models of Multiple-System Atrophy

  2015cites this paper
• Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?

  2015cites this paper
• Mutation Analysis of COQ2 in Chinese Patients with Cerebellar Subtype of Multiple System Atrophy

  2015cites this paper
• A cytosine‐thymine (CT)‐rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression

  2015cites this paper
• Association of the COQ2 V393A Variant with Parkinson's Disease: A Case-Control Study and Meta-Analysis

  2015cites this paper
• The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism☆

  2015cites this paper
• Genetic Variants of SNCA Are Associated with Susceptibility to Parkinson’s Disease but Not Amyotrophic Lateral Sclerosis or Multiple System Atrophy in a Chinese Population

  2015cites this paper
• Variants associated with Gaucher disease in multiple system atrophy

  2015cites this paper
• Multiple-system atrophy.

  2015cites this paper
• Link between the SNCA gene and parkinsonism.

  2015cites this paper
• Models of multiple system atrophy.

  2015cites this paper
• Multiple system atrophy: the application of genetics in understanding etiology

  2015cites this paper
• SNP rs11931074 of the SNCA gene may not be associated with multiple system atrophy in Chinese population

  2015cites this paper
• Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders

  2015cites this paper
• SNCA rs3822086 C>T Polymorphism Increases the Susceptibility to Parkinson's Disease in a Chinese Han Population

  2015cites this paper
• DNAJC13 genetic variants in parkinsonism

  2015cites this paper
• The Role of Calcium in Alpha-Synuclein Aggregation : A Potential Mechanism of Neurodegeneration

  2015influential citation
• Genetics of Atypical Parkinsonism

  2015cites this paper