Abstract Details

Multiple lines of evidence support the association of lysosomal genes with Parkinson’s disease (PD). Homozygous mutations in ARSA may cause a lysosomal storage disease- metachromatic leukodystrophy. A recent study demonstrated direct interaction of ARSA with alpha-synuclein in the cytosol. However, the genetic association between ARSA and PD remains controversial. In the current study, we aim to evaluate the association between rare ARSA variants and PD.

To examine whether rare variants in ARSA are associated with PD.

To study the association of rare variants in ARSA with PD, we performed burden analysis in three cohorts sequenced at McGill university (McGill,Columbia and Sheba cohorts) with a total of 2,421 PD patients and 1,625 controls. The ARSA gene was targeted using molecular inversion probes. Additionally, we used UK biobank (UKBB) whole-exome-sequencing data including 602 PD patients and 140,207 controls of European descent. To analyze rare variants (MAF<0.01), an optimized-sequence Kernel-association test (SKAT-O) was performed. We separately analyzed the burden of rare, coding, functional variants, and variants with a CADD score≥20. We performed a meta-analysis between the cohorts sequenced at McGill and we used the UKBB data as a replication cohort.

Burden analysis demonstrated an association for functional variants with PD in the McGill and Sheba cohorts (p=0.003,p=0.017). This finding was confirmed in the meta-analysis (p=0.006) and in the UKBB (p=1.47e-05). Moreover, we discovered significant associations between all rare variants and PD across all three discovery cohorts and in the UKBB (p=0.03). However, this association was not confirmed in the meta-analysis. Additionally, variants with high CADD score were associated with PD in the Columbia and McGill cohorts (p=0.005 and p=0.017), whereas no association was found in the meta-analysis and in the UKBB cohort.

Rare functional variants may be associated with PD. Further replication in other non-European cohorts is required along with the functional analysis.