Abstract
Objective: To determine whether an aggregate burden of variants in lysosomal storage disorder (LSD) genes besides GBA are associated with Parkinson’s disease (PD) susceptibility.
Background: Parkinson’s disease is a common neurodegenerative disorder with evidence for substantial genetic etiology; however, the risk alleles identified to date explain only a small portion of PD heritability. Pathogenic variants in GBA, which cause Gaucher disease, are potent risk factors for PD, and other LSD genes have also been implicated. However, there are more than 50 other known LSDs, and the responsible genes have yet to be systematically evaluated for contribution to PD risk.
Design/Methods: PD patients were recruited from academic medical centers across the United States and Europe. Sequence kernel association testing was used to examine the burden of variants within 54 genes that cause LSDs, leveraging whole exome sequencing (WES) data in a discovery cohort with over 2,900 subjects. Variants were classified based on minor allele frequency and potential pathogenicity. For replication, we interrogated two independent datasets, including 605 additional subjects with WES and more than 12,000 with exome-wide genotyping. Secondary analyses were performed to determine the LSD genes most likely to be contributing to the aggregate association signal.
Results: In the discovery cohort, we demonstrate a significant burden of rare, likely damaging LSD gene variants robust to the exclusion of GBA. Evidence for a variant burden within LSD genes was also seen in the replication cohorts. Secondary analyses confirm associations at the GBA, SMPD1, and SCARB2loci, and newly implicate CTSD, SLC17A5, and ASAH1 as candidate PD susceptibility genes.
Conclusions: We identify several promising new PD susceptibility genes, reinforcing the importance of lysosomal mechanisms in PD pathogenesis. We propose an oligogenic model of PD, in which multiple genetic hits may act in combination to degrade lysosomal function, enhancing disease susceptibility.
Disclosure: Dr. Robak has nothing to disclose. Dr. Jansen has nothing to disclose. Dr. van Rooij has nothing to disclose. Dr. Uitterlinden has nothing to disclose. Dr. Kraaj has nothing to disclose. Dr. Heutink has nothing to disclose. Dr. Shulman has nothing to disclose.
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