No genetic evidence for SLC7A11 involvement in Parkinson's Disease

Abstract

BackgroundThe cystine/glutamate antiporter encoded by SLC7A11 maintains cellular redox balances and lysosomal pH. Recent molecular evidence suggested that SLC7A11 may be involved in Parkinsons disease (PD). However, the genetic contribution of SLC7A11 to PD susceptibility remains unclear. MethodsWe analysed whole-genome sequencing data from the Accelerating Medicines Partnership-Parkinsons 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. ResultsNo 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. DiscussionThese findings suggest that genetic variation in SLC7A11 or its expression are unlikely to have a major role in PD susceptibility. Plain Language TitleWe did not find evidence that the SLC7A11 gene is involved in Parkinsons disease Plain Language SummaryParkinsons Disease (PD) is a brain disorder where both genetic and environmental factors play a role in a persons risk of developing PD. Recent studies suggested that a gene called SLC7A11 may be involved in PD as it helps to decrease the factors that increase the chances of getting PD, such as cell stress and lysosome function. In this paper, we tested the genetic importance of SLC7A11 and PD by analysing data from two data sets: the Accelerating Medicines Partnership-Parkinsons Disease study and the UK Biobank. Together, we studied both rare and common genetic changes of SLC7A11 in approximately 5,300 people with PD and 35,000 without. We also looked at whether these genetic changes affected GCase, an enzyme important for lysosomal function, and whether there was a difference in SLC7A11 activity in different brain regions. We found no evidence that genetic changes in SLC7A11 were associated with PD risk or GCase enzyme activity. Some genetic changes affected SLC7A11 expression in the brain, but these changes were not linked with PD. Overall, our findings suggest that inherited genetic differences in SLC7A11 are unlikely to play a major role in PD risk.