TMEM175, SCARB2 and CTSB associations with Parkinson's disease risk across populations.

Background: Lysosomal dysfunction is known to play an important role in Parkinson's disease (PD). Variants in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1), involved in sphingolipid metabolism, are common risk factors for PD. The PD genome-wide association study (GWAS) successfully identified other common variants associated with lysosomal mechanism, in the genes transmembrane protein 175 (TMEM175), Scavenger Receptor Class B Member 2 (SCARB2), and Cathepsin B (CTSB). Aim: This study aims to explore the association between common and rare variants in these lysosomal genes with PD across several populations. Methods: We leveraged large cohorts from the Global Parkinson's Genetics Program (GP2) Neurobooster array release 10 dataset including 33,813 cases and 18,714 controls from 11 ancestries, and the Accelerating Medicines Partnership Parkinson's Disease (AMP-PD) whole genome sequencing (WGS) release 4 dataset, which contains 3,188 cases and 4,104 controls. Previous GWAS hits in TMEM175, SCARB2, and CTSB in European ancestry cohort were evaluated and conditional analysis (GCTA-COJO) was applied to identify novel independent common genetic variants across populations. A burden analysis (SKAT-O) was performed to examine association between rare variants in these genes and PD risk. Subsequently, a single-variant-based test was carried out to identify variants with excessive burden in PD cohorts. Results: Our common variant association analysis revealed significant associations with PD risk in European ancestry for all known genetic risk variants across the three lysosomal related genes studied: TMEM175 (rs34311866 and rs34884217), SCARB2 (rs6812193 and rs6825004), CTSB (rs1293298). We confirmed p.M393T as a genome-wide significant signal, independent of all other variants within the TMEM175 locus in the GP2-European cohort. In the European population, a novel independent signal, rs11547135 in SCARB2 gene, was identified. The SKAT-O analysis linked PD to SCARB2 in GP2- African American/Ashkenazi Jewish/East Asian cohorts. Single-variant-based tests identified rare coding association signals in SCARB2 in GP2- African American cohort (2 missense: p.Tyr284Ser and p.Val149Met, 3 synonymous: p.Glu230=, p.Ala162=, and p.Leu76=); in GP2-Ashkenazi Jewish cohort (1 missense: p.Met159Val) and in the GP2- Central Asian cohort (2 missense: p.Asp194Asn and p.Ile144Leu). Conclusion: Our analysis validates previous findings and extends them across diverse populations. Our study reinforces the association of lysosomal gene variants with PD risk, revealing heterogeneity in genetic associations across populations. Genotyping array data and WGS data in diverse populations offer a resource to further understanding of genetic risk and should be pursued in the future to improve statistical power.