Comprehensive analysis of SLC17A5 variants in large European cohorts reveals no association with Parkinson's disease risk

Abstract

Background

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. Aging is the primary risk factor, with both rare and common genetic variants playing a role. Previous studies have implicated lysosomal storage disorder (LSD)-related genes, including SLC17A5, in PD susceptibility.

Objective

This study aimed to investigate the association of SLC17A5 variants, including rare and common variants and the FSASD-associated p.Arg39Cys missense variant, with PD risk in large European ancestry cohorts.

Methods

Rare variant burden analyses were performed at minor allele frequency (MAF) thresholds of ≤1 % and ≤0.1 % in 7,184 PD cases and 51,650 controls using whole-genome and whole-exome sequencing data. Association testing of the p.Arg39Cys variant was conducted across five cohorts, encompassing both Finnish and non-Finnish Europeans. Common variant associations were examined using summary statistics from the largest European GWAS of PD.

Results

No significant association was observed between rare SLC17A5 variants and PD at either MAF threshold. The p.Arg39Cys variant, though enriched in Finnish Europeans, showed no significant association with PD across several cohorts. Similarly, common SLC17A5 variants (MAF ≥1%) were not associated with PD risk.

Conclusion

Our findings do not support a role for SLC17A5 variants in PD susceptibility. While lysosomal dysfunction is central to PD pathogenesis, its contribution appears pathway-specific, with SLC17A5 unlikely to influence risk. Larger, multiethnic studies and functional analyses are needed to further investigate sialic acid metabolism in PD and related disorders.