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.

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

“…Although studies of this scope may be possible in the near future, rather than focusing on individual genes where statistical power is more limited, we have pursued a complementary approach examining aggregate genetic risk among 54 LSD genes. Indeed, among ∼3,000 PD cases and controls with exome sequencing data, we discovered a significant “burden” of putative damaging variants among this LSD gene set . This result was robust to the exclusion of GBA1 and was consistent in two independent data sets, suggesting that other LSD genes besides GBA1 likely contribute to PD risk.…”

“…This result was robust to the exclusion of GBA1 and was consistent in two independent data sets, suggesting that other LSD genes besides GBA1 likely contribute to PD risk. Importantly, more than half of our PD cohort (56%) had more than one LSD gene variant, and 21% carried two or more potential risk alleles in multiple LSD genes . These results therefore support the possibility of an oligogenic risk model for PD, in which multiple genetic hits act in combination to degrade cellular metabolism, enhancing disease susceptibility (Fig.…”

Genetic risk factors in Parkinson’s disease

“…The most recent meta-analysis replicated the signals at these lysosomal-associated loci but also nominated three new lysosomal-associated genes: CTSB (cathepsin B), ATP6V0A1 (ATPase H + transporting V0 subunit a1), and GALC (galactosylceramidase). Interestingly, a recent study has not only replicated the association between the outlined risk loci but also addressed an enrichment of rare variants in additional novel lysosomal genes (Robak et al 2017, in press). Robak et al tested the hypothesis that lysosomal gene variants are enriched in PD.…”

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

“…Variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are among the most common risk factors for PD, found in 3%‐20% of PD patients from different populations . Recently, mutations in another lysosomal gene involved in sphingolipid metabolism, SMPD1 , which encodes the lysosomal enzyme acid sphingomyelinase (ASMase), have also been associated with an increased risk for PD . In the Ashkenazi Jewish population, specific Niemann‐Pick type A (NPA)‐causing SMPD1 mutations, p.L302P (also called p.L304P) and p.fsP330 (also called p.F333Sfs*52 or c.996delC), were associated with PD in 2 independent studies .…”