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

Abstract

Genome-wide association study of Parkinsons disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinsons Genetics Program (GP2) (33,813 cases and 18,714 controls from 11 ancestries), and the Accelerating Medicines Partnership Parkinsons Disease (AMP-PD) whole genome sequencing (3,188 cases and 4,104 controls). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p.M393T as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense and synonymous variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.