rs356182 — SNCA

SNCA rs356182 — A Key Parkinson's Disease Risk Variant with a Complex Phenotypic Profile

The rs356182 variant sits approximately 19 kilobases downstream of the SNCA gene¹¹ SNCA gene
Alpha-synuclein (SNCA) is the first gene linked to Parkinson's disease and encodes a protein that forms the pathological hallmark of PD — Lewy bodies, in a brain-specific regulatory region marked by H3K27Ac histone modifications. This variant is one of the most statistically significant genetic associations with Parkinson's disease²² This variant is one of the most statistically significant genetic associations with Parkinson's disease
With a meta-analysis p-value of 1.85 × 10⁻⁸², rs356182 ranks among the strongest non-coding PD risk variants, consistently identified across multiple large-scale genome-wide association studies³³ multiple large-scale genome-wide association studies. The G allele increases PD risk with an odds ratio of 1.34 to 1.47⁴⁴ odds ratio of 1.34 to 1.47 depending on the population studied, and is robustly represented at approximately 37% frequency globally.

What makes rs356182 particularly interesting is that it doesn't follow a simple story. The risk allele (G) increases your chances of developing Parkinson's, but if you do develop the disease with GG genotype, you're more likely to have a tremor-predominant form with slower motor progression⁵⁵ tremor-predominant form with slower motor progression compared to the more aggressive postural instability and gait disorder (PIGD) phenotype. This paradox — higher disease risk but milder disease course — reveals the complexity of how this variant influences neurodegenerative processes.

The Mechanism

rs356182 resides within a genetic enhancer active in brain tissue, and the protective A allele creates a binding site for the transcription factor FOXO3⁶⁶ transcription factor FOXO3, while the risk G allele disrupts this binding. The traditional assumption was that this variant simply modulates alpha-synuclein levels, since it's near the SNCA gene. However, breakthrough CRISPR studies have revealed a more nuanced picture⁷⁷ breakthrough CRISPR studies have revealed a more nuanced picture: the protective A allele promotes normal neuronal differentiation and actually increases SNCA expression, while the risk G allele impairs neuronal development and reduces SNCA expression. This is counterintuitive — you'd expect higher alpha-synuclein to be worse for Parkinson's risk.

The resolution to this paradox likely lies in timing and context. The risk G allele appears to compromise dopaminergic neuron development during embryonic neurodevelopment⁸⁸ embryonic neurodevelopment
The effects manifest during fetal brain development, creating a diminished dopaminergic neuron population, leaving fewer neurons to spare when age-related degeneration begins decades later. Meanwhile, in adults who already have PD, having the GG genotype (which reduces alpha-synuclein expression in the cerebellum) may slow the accumulation of toxic protein aggregates, explaining the slower motor progression observed in clinical studies⁹⁹ slower motor progression observed in clinical studies.

The Evidence

A large case-control study in 2,205 Han Chinese participants¹⁰¹⁰ A large case-control study in 2,205 Han Chinese participants
Cheng et al. SNCA rs356182 variant increases risk of sporadic Parkinson's disease in ethnic Chinese. Journal of the Neurological Sciences, 2016 found that the G allele was significantly overrepresented in PD patients (OR=1.470, p=2.3×10⁻⁸), with the GG genotype showing the strongest association (OR=1.620). This replicated findings from Caucasian populations, establishing rs356182 as a cross-ethnic risk factor.

A multi-site study of 810 Parkinson's patients¹¹¹¹ A multi-site study of 810 Parkinson's patients
Cooper et al. Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. Annals of Clinical and Translational Neurology, 2017 demonstrated that the GG genotype correlates with more tremor-predominant motor symptoms and predicts a 1-point per year slower UPDRS-III motor score progression. The variant was also associated with decreased SNCA expression in cerebellar tissue (p=0.005), suggesting region-specific effects on gene regulation.

The most mechanistically revealing study¹²¹² The most mechanistically revealing study
Prahl et al. The Parkinson's disease variant rs356182 regulates neuronal differentiation independently from alpha-synuclein. Human Molecular Genetics, 2023 used CRISPR to create precise hemizygous deletions at rs356182 in dopaminergic neuron cell models. Transcriptional profiling revealed that hundreds of genes involved in neurogenesis and axonogenesis were differentially expressed based on the allele present, with only minimal overlap with genes affected by SNCA knockout. This suggests rs356182 confers PD risk largely through mechanisms independent of alpha-synuclein levels.

A comprehensive meta-analysis¹³¹³ A comprehensive meta-analysis
Pihlstrøm et al. A comprehensive analysis of SNCA-related genetic risk in sporadic Parkinson disease. Annals of Neurology, 2018 identified rs356182 as one of at least three independent association signals at the SNCA locus, demonstrating that multiple genetic mechanisms at this locus contribute to PD risk in a non-redundant fashion.

Practical Implications

While there's no gene therapy or drug that specifically targets rs356182, the mechanisms it influences — neuronal health, oxidative stress, mitochondrial function, and dopamine system integrity — are all modifiable through lifestyle interventions. The evidence is strongest for aerobic exercise and antioxidant support.

Regular aerobic exercise demonstrates neuroprotective effects in Parkinson's models¹⁴¹⁴ Regular aerobic exercise demonstrates neuroprotective effects in Parkinson's models, improving mitochondrial function, reducing oxidative protein damage, and boosting neurotrophic factors like BDNF and GDNF in the substantia nigra. Exercise activates the Nrf2-ARE antioxidant response pathway, upregulates endogenous antioxidant enzymes, and may help preserve the dopaminergic neuron population that could be developmentally compromised by the G allele.

Dietary antioxidants — particularly beta-carotene and vitamin E¹⁵¹⁵ beta-carotene and vitamin E — have shown inverse associations with PD risk in prospective cohort studies. While these studies weren't stratified by rs356182 genotype, the biological rationale is sound: alpha-synuclein pathology generates oxidative stress, and individuals with variants affecting SNCA-related pathways may benefit more from antioxidant support.

For those with existing Parkinson's disease, knowing your rs356182 genotype may offer prognostic information. The GG genotype appears to predict a slower, more tremor-dominant course, which generally has a better prognosis and responds well to dopaminergic medications. However, this is population-level data — individual disease trajectories vary enormously based on other genetic factors, environmental exposures, and treatment responses.

Interactions

rs356182 is one of multiple independent SNCA risk variants. Other key variants include rs356219 (located in the promoter region) and rs356165, though these show minimal linkage disequilibrium with rs356182¹⁶¹⁶ these show minimal linkage disequilibrium with rs356182, meaning they segregate independently and can combine to increase risk additively. Individuals carrying risk alleles at multiple SNCA positions show incrementally higher PD susceptibility.

Beyond SNCA, gene-gene interactions have been documented between rs356219 (a related SNCA variant) and variants in LRRK2 and GAK genes¹⁷¹⁷ gene-gene interactions have been documented between rs356219 (a related SNCA variant) and variants in LRRK2 and GAK genes, suggesting that SNCA-pathway risk is modified by other Parkinson's genes. While specific studies haven't examined rs356182 in combination with LRRK2 or GBA variants, the biological pathways overlap — LRRK2 affects alpha-synuclein neurotoxicity and GBA mutations compromise lysosomal degradation of alpha-synuclein. Individuals with multiple risk variants across these pathways likely face compounded neurodegeneration risk, though the precise combined effects remain under investigation. Similarly, in carriers of LRRK2 mutations, the SNCA rs356219 variant modifies age of onset by approximately 4 years¹⁸¹⁸ in carriers of LRRK2 mutations, the SNCA rs356219 variant modifies age of onset by approximately 4 years, suggesting that SNCA variants interact with other PD genetic risk factors to influence disease timing and phenotype.