rs356219

This meta-analysis of 19 studies (comprising 31 case-control studies) examined 10 SNCA gene polymorphisms and Parkinson's disease (PD) risk. Eight SNPs showed significant associations with PD: rs181489 (OR 1.678, Caucasian), rs356186 (protective, OR 0.653, Caucasian), rs356219 (OR 1.523, Caucasian), rs894278 (OR 1.493, Asian), rs2583988 (OR 1.409, Caucasian), rs2619364 (OR 1.346, Caucasian), rs10005233 (OR 1.359 in dominant model, Caucasian), and rs11931074 (OR 1.798 overall). Two SNPs (rs2619363 and rs2737029) showed no significant association. Results indicate SNCA is a common susceptibility marker for PD in both Asian and Caucasian populations.

German doctoral dissertation investigating genetic risk factors for Parkinson's disease in the Icelandic population. The thesis comprises three studies: (1) Analysis of EIF4G1 gene mutations (p.Ala502Val, p.Arg1205His) in 2,146 European PD patients and 93,698 Icelandic samples showing EIF4G1 is neither a strong nor common risk factor; (2) Case-control study of PARK2 copy number variants in 1,415 PD patients versus 40,474 controls (≥65 years) demonstrating heterozygous PARK2 CNV carriers have significantly increased PD risk (OR=1.69, p=0.03); (3) Investigation of common genetic PD risk variants' effects on LRRK2 G2019S mutation carriers.

This is a German dissertation containing two peer-reviewed association studies on Parkinson's disease genetics. The first study found EIF4G1 is neither a strong nor common PD risk factor in European cohorts (2146 patients), with the p.Arg1205His variant showing no significant association (OR=1.3, p=0.50) in Icelandic population. The second study demonstrated heterozygous PARK2 CNV carriers have increased PD risk in Iceland (1415 cases vs 40474 controls, OR=1.7, p=0.03), supported by meta-analysis.

Meta-analysis of five Parkinson disease GWAS studies (4,238 cases, 4,239 controls) identifying a novel susceptibility locus at RIT2 (rs12456492, OR=1.19, p=2×10⁻¹⁰). Multiple independent associations detected at SNCA (rs356220, rs356198), GBA (E326K and N370S variants), and other loci including GAK/DGKQ, MAPT, and HLA region. Results replicated in 3,738 cases and 2,111 controls.

This large case-control study of 5,302 Parkinson's disease cases and 4,161 controls from 15 sites examined the independent and joint effects of SNCA and MAPT genes. Four SNCA SNPs (rs2583988, rs181489, rs356219, rs11931074) and two MAPT SNPs (rs1052553, rs242557) were all significantly associated with PD risk, with SNCA variants at the 3' end showing the strongest associations. Notably, no evidence of statistical interaction was found between SNCA and MAPT SNPs on either multiplicative or additive scales, despite their independent contributions to PD susceptibility.

This replication study of 1,445 Parkinson's disease patients and 1,161 controls from Northern Spain confirms MAPT (rs1800547, p=3.1×10⁻⁴, OR=0.79) and SNCA (rs356219, p=5.5×10⁻⁴, OR=1.23) as PD susceptibility genes, but fails to replicate PARK16, PARK17, and PARK18 loci (p values 0.09-0.88). The findings suggest that PARK16-18 may harbor population-specific effects or require larger sample sizes for detection in European-derived populations.

This case-control association study of 1,956 Parkinson's disease (PD) patients and 2,112 controls identified rs356219 (OR=1.41, 95% CI 1.28-1.55, p=1.6×10⁻¹²) as a major genetic susceptibility variant for PD located ~9 kb downstream of SNCA. The risk allele was associated with increased plasma α-synuclein levels in PD cases (p=0.005), suggesting the functional variant tagged by rs356219 may upregulate SNCA expression in a dose-dependent manner, independent of the previously known REP1 promoter repeat polymorphism.

A genome-wide survival meta-analysis of 3,923 Parkinson's disease patients identified three genome-wide significant loci associated with progression to Parkinson's disease dementia: APOE rs429358 (HR=2.41, P=2.32×10−15), LRP1B rs80306347 (HR=3.23, P=7.07×10−9), and BBS9 rs78294974 (HR=3.90, P=3.59×10−8). The study reveals APOE ε4 and LRP1B as major risk factors and suggests the amyloid pathway's involvement in dementia development.

Large European association study evaluating EIF4G1 mutations in Parkinson's disease across 2,146 PD patients and 93,698 Icelandic population samples. The p.Arg1205His variant (rs112176450) showed no significant association with PD risk (OR=1.3, p=0.50), and p.Ala502Val was not detected. The study concludes EIF4G1 is neither a strong nor common PD risk factor and should not be recommended for clinical diagnostic testing.