To date, GBA  gene variations are the most common large-effect genetic factor linked to Parkinson’s disease (PD). However, it was still unknown why people with the identical GBA variation experience neurodegeneration and Parkinson’s disease. As a result, researchers compared the burden of deleterious variations in lysosomal storage disorders (LSD) genes in PD patients against asymptomatic people, all bearers of GBA harmful mutations.

To test 305 patients and 207 controls, they employed a bespoke next-generation sequencing panel that included 50 LSD genes (discovery cohort). Replication and meta-analysis were carried out in two replication cohorts of GBA -variant carriers, each consisting of 250 patients and 287 controls with accessible exome or genome data. 

Statistical analysis in the discovery cohort indicated that patients had a considerably higher burden of detrimental mutations in LSD genes (P=0.0029). Furthermore, the findings show that the two most powerful modifiers of GBA  penetrance are a second variation in GBA  (5.6% vs. 1.4%, P=0.023) and polymorphisms in genes causing mucopolysaccharidoses (6.9% vs. 1%, P=0.0020). The meta-analysis corroborated the findings, with pooled odds ratios of 1.42 (95% CI=1.10-1.83, P=0.0063), 4.36 (95% CI=2.02-9.45, P=0.00019), and 1.83 (95% CI=1.04-3.22, P=0.038) for variations in LSD, GBA , and mucopolysaccharidosis genes, respectively.

The discovery of genetic abnormalities in lysosomal genes that increase the likelihood of Parkinson’s disease may have significant consequences for patient classification in future treatment trials.

Reference: movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.28987