No genetic evidence for SLC7A11 involvement in Parkinson's Disease

Background: The cystine/glutamate antiporter encoded by SLC7A11 maintains cellular redox balances and lysosomal pH. Recent molecular evidence suggested that SLC7A11 may be involved in Parkinson's disease (PD). However, the genetic contribution of SLC7A11 to PD susceptibility remains unclear. Methods: We analysed whole-genome sequencing data from the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) and United Kingdom Biobank (UKBB) cohorts, comprising of 5,5375 cases and 35,002 controls. Rare variant burden analyses were performed using SKAT-O and MetaSKAT. Common-variant associations with PD risk and glucocerebrosidase (GCase) enzyme activity were assessed with regional linkage disequilibrium plots using previous GWAS summary statistics. Gene expression effects were examined through brain-specific expression quantitative trait loci (eQTL) data from GTEx v7. Colocalization analyses and regional association plots were generated to visualize and compare GWAS and eQTL signals across the SLC7A11 locus. Results: No rare or common SLC7A11 variants were associated with PD or GCase activity, including variants that had strong effects on SLC7A11 expression in relevant brain regions. Discussion: These findings suggest that genetic variation in SLC7A11 or its expression are unlikely to have a major role in PD susceptibility.