Identification and stratification of Parkinson’s patients lacking
Cure Parkinson's
St Vincent's Hospital Sydney
GBA mutations, which impact lysosomal enzyme GCase activity, are numerically the most significant genetic risk factor for Parkinson’s disease (PD). However, the incomplete penetrance of Parkinson’s amongst GBA carriers is surprisingly low and raises the possibility of genetic modifiers that influence GBA expression and GCase activity. This prospect is supported by reports that patients with idiopathic PD lacking GBA mutations have also been found to have reduced levels of GCase levels. To investigate this idea further, a genome-wide search was conducted of >31million common SNPs for trans-eQTLs (Expression quantitative trait loci) for GBA expression in either the substantia nigra or the cortex identified significant distal SNP-GBA associations for two loci in the substantia nigra and four loci in the cortex, with the six loci located on different chromosomes from each other and GBA. Importantly the variants either increase (SN 1; cortex 2) or decrease (SN 1; cortex 2) GBA expression. Therefore, independent assortments of these common regulatory variants could result in combinations of variant haplotypes that produce a range of GBA expression levels in the SN and/or cortex that could modulate the phenotype of GBA carriers. These consequences of regulatory variant combinations would also modulate GBA expression in individuals lacking GBA mutations, with the prediction that reduced GBA expression is a significant disease contributor in specific PD patients. If identifiable, these idiopathic patients would be best suited to benefit from GBA therapeutics. It is predicted here that haplotype combinations of the 3 regulatory variants that decrease GBA expression in the SN (rs1A) and/or cortex (rs3C & rs4D) will: 1. be over-represented in patients relative to healthy individuals 2. have earlier disease onset of movement and cognitive impairment respectively 3. have elevated disease progression in motor and cognitive symptoms. Conversely, haplotype combinations of the 3 regulatory variants that increase GBA expression in the SN (rs2B) and/or cortex (rs5E & rs6E) will be over-represented in healthy individuals. This project aims to validate these variants using larger datasets (the NIH Accelerated Medicine Partnership PD (AMP PD)) and assess the clinical outcomes of individuals carrying the variants. The ultimate goal is to apply the knowledge gained in patient selection practices for future clinical PD trials of therapies targeting GBA (such as ambroxol).
2.1 Biological and endogenous factors