Association of SNCA Parkinson's Disease Risk Polymorphisms With Disease Progression in Newly Diagnosed Patients

Abstract

Objectives: To evaluate the impact of SNCA polymorphisms originally identified as risk factors for Parkinson's disease (PD) on the clinical presentation and progression of the disease in a large cohort of population-based patients with incident PD.Methods: Four hundred thirty-three patients and 417 controls from three longitudinal cohorts were included in the study. Disease progression was recorded annually for up to 9 years using the Unified Parkinson's Disease Rating Scale (UPDRS) or Mini-Mental State Examination. Genotypes for five variants within the SNCA locus (rs2870004, rs356182, rs5019538, rs356219, and rs763443) were determined. We studied the association between each variant and disease progression using linear mixed-effects regression models.Results: The clinical profile of the patients with PD at the point of diagnosis was highly uniform between genotype groups. The rs356219-GG genotype was associated with a higher UPDRS II score than A-allele carriers (β = 1.52; 95% confidence interval 0.10–2.95; p = 0.036), but no differences were observed in the rate of progression of the UPDRS II scores. rs356219-GG was also associated with a faster annual change in Mini-Mental State Examination score compared with A-carriers (β = 0.03; 95% confidence interval 0.00–0.06; p = 0.043).Conclusions: We show that the known PD-risk variant rs356219 has a minor effect on modifying disease progression, whereas no differences were associated with rs2870004, rs356182, rs5019538, and rs763443. These findings suggest that SNCA variants associated with PD risk may not be major driving factors to the clinical heterogeneity observed for PD.

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10‐Year Population‐Based Study

“…We show a small effect of rs356219 on global cognitive decline before adjustment for multiple comparisons, replicating our previous finding using a subset of 443 patients included in this current work. 30 A larger, independent cohort will be required to validate this result, but given the small effect size, the impact of this variant is unlikely to be clinically meaningful. Few studies have reported the impact of MAPT or rs356219 on the progression to dementia.…”

“…For primary analysis, patients were grouped by genotype based on previous studies: APOE , carriers of ε4 allele versus non‐carriers 6 ; GBA , carriers of any GBA mutation versus non‐carriers 6 ; MAPT , carriers of H1/H1 versus H2 haplotype 14 ; and SNCA rs356219, carriers of GG genotype versus A‐allele 30 . Primary analyses were corrected for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) method at FDR < 0.05.…”

“…For primary analysis, patients were grouped by genotype based on previous studies: APOE , carriers of ε4 allele versus non-carriers 6 ; GBA , carriers of any GBA mutation versus non-carriers 6 ; MAPT , carriers of H1/H1 versus H2 haplotype 14 ; and SNCA rs356219, carriers of GG genotype versus A-allele. 30 Primary analyses were corrected for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) method at FDR < 0.05. For secondary analysis, carriers of APOE -ε4 were subdivided into carriers of one or two ε4 alleles, and GBA carriers were subdivided into carriers of PD risk or mild mutations, severe mutations, or variants of unknown significance.…”

Genetic Elements at the Alpha-Synuclein Locus

“…Again, rs2870004 failed to reach significance in the Nalls et al ( 2019) meta-analysis. Like rs763443, the only other publication which references this SNP is the analysis of disease heterogeneity, and again they found that this SNP failed to explain any of the disease heterogeneity (Szwedo et al, 2020). GTEx data suggests that rs2870004 is not significantly correlated to SNCA or MMRN1 expression within the substantia nigra (Supplementary Table 2).…”

“…The only other notable reference to this SNP is an analysis of disease heterogeneity based on genotype of the risk-signals identified by Pihlstrom et al (2018) . They found that this SNP failed to explain any of the disease heterogeneity amongst a large cohort of newly diagnosed PD patients ( Szwedo et al, 2020 ). According to GTEx, rs763443 does not significantly correlate to SNCA or MMRN1 expression in the substantia nigra ( Supplementary Table 2 ).…”