Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease

Abstract

Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

Keywords: Parkinson’s disease; genetics; lysosomal storage disorders; whole exome sequencing.

Figure 1

Overall analytic strategy. (Left) Variant categories. Because the number, frequency, and effect sizes of Parkinson’s disease risk variants remains incompletely defined, our analyses considered three nested categories based on increasing variant pathogenicity: (1) all non-synonymous variants (Nonsyn); (2) likely damaging variants based on combined annotation dependent depletion (CADD) score; and (3) loss-of-function (LoF) variants. Based on the known prevalence of Parkinson’s disease and incomplete penetrance documented for many risk alleles, we also considered two frequency thresholds, including rare (MAF < 1%) and somewhat more common (MAF < 3%) variants. (Right) Analysis flow chart. The SKAT-O was initially performed for the complete LSD gene set in the IPDGC discovery cohort, considering each variant category separately. For those categories with a significant SKAT-O association in the full gene set, a secondary analysis was performed excluding all GBA variants in order to confirm the involvement of additional genes. This was repeated in each of the replication cohorts (PPMI and NeuroX). Lastly, to highlight those loci driving associations detected in the gene set, secondary analyses were performed in the IPDGC cohort using SKAT-O to evaluate variants in each LSD gene independently.

Figure 2

Distribution of LSD variants in the IPDGC cohort. The number of likely damaging LSD variants (MAF < 3%, CADD C-score ≥ 12.37) per individual is shown versus the proportional representation in the IPDGC discovery cohort. Cases (red) and controls (blue) are plotted separately. Many individuals harbour multiple LSD alleles, and the distribution is right-skewed among Parkinson’s disease cases. The analysis considers variants in all 54 LSD genes. Supplementary Fig. 2 shows a similar plot restricted to the five top driver genes.