In this study, we have demonstrated that genetic variants within the SNCA locus are associated with increased risk for development of MSA. These data represent the first genetic variants convincingly identified for patients with MSA. This study is important in that genetic factors play a greater role in the pathogenesis of MSA, which entity primarily suggests thought of as sporadic in occurrence. The veracity of our findings is underscored by the strength of the association that clearly exceeded the conservative Bonferroni threshold for statistical significance, by the successful replication of our findings in an independent cohort, and by the role that SNCA is already known to play in the disease process based on neuropathological findings.4–6
Previous studies (including sequencing of SNCA coding sequence, gene dosage measurements, microsatellite testing, and haplotype studies) have failed to identify significant association of SNCA variants with MSA.12–16
These negative results can be explained by the smaller sample sizes of these studies, and by the fact that none of the SNCA risk variants identified in our study was tested. Our replication of the association between SNCA variants and MSA in an independent patient and control cohort indicates that population stratification was unlikely to be falsely driving the finding. The failure to replicate our findings in MSA-P and MSA-C clinical subgroups was likely due to small sample size and the diagnostic uncertainty inherent to clinical criteria.17
A combination of these factors would negatively impact the power to detect association within these patient subsets, and studies of larger cohorts will be required to dissect the true pathogenic role of SNCA variants within each of these clinical categories. In contrast, analysis in the smaller, but diagnostically accurate, subset of pathology-proven MSA cases clearly demonstrates that SNCA variants are associated with increased risk for disease.
The significant associations with increased risk for MSA were most clearly observed under the recessive model. However, it is possible that the relatively small size of our case–control cohort was powered only to identify individuals carrying two risk alleles, but that an undetected additive risk at these loci exists. Additional studies involving larger patient cohorts are required to determine whether persons with a single copy of the risk allele are at increased risk for development of MSA.
How does genetic variation at the SNCA locus confer an increased risk for development of MSA? Previous sequence analysis of SNCA coding sequence failed to identify pathogenic mutations; thus, direct alteration of the amino acid sequence is considered an unlikely mechanism of disease.12,16
The most plausible explanation, therefore, would be a change in gene expression regulation. This explanation is supported by the observation that duplication or triplication of SNCA leads to glial cytoplasmic inclusion formation in the brains of affected individuals, and that in some subjects, the clinical presentation resembles a MSA phenotype.4–6
A modest alteration in gene expression levels, although pathogenic in a given individual, may have escaped detection in previous SNCA expression studies of small sample size.18–20
The identified risk variants may also alter the splicing pattern of SNCA in a pathogenic manner, or alter SNCA messenger RNA processing, or additional genetic factors may be responsible for the different manners of synuclein accumulation in PD and MSA.
How do the results of our candidate SNP association study in MSA compare with our genome-wide association study in PD? We identified significant association with the SNCA locus in both diseases.9
The odds ratio associated with carrying a single risk allele of the SNCA SNP rs3857059 was 1.3 in both diseases (95% CI in PD: 1.2–1.5; 95% CI in MSA: 1.1–1.6), whereas the odds ratio for homozygous carriers was 3.8 (95% CI: 2.4–5.9) in PD and 5.9 (95% CI: 3.2–10.9) in MSA.
In summary, our study has conclusively demonstrated that genetic variants in SNCA play a role in the pathogenesis of MSA, and that these genetic factors overlap with those found in PD. These data support the general notion that variability at the gene that encodes the major pathologically deposited species is a risk factor in neurological diseases involving protein deposition21
but highlights that often large sample sizes are required to see such an effect. Additional genetic loci undoubtedly remain to be identified in the pathogenesis of this fatal neurodegenerative disease.