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

Abstract

Genome-wide association study of Parkinson's 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 Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr 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 variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.

Fig. 1. Forest plot illustrating the association between Parkinson’s disease risk and the five studied genetic variants in three lysosomal related genes across ten ancestries.

a TMEM175 p.M393T (rs34311866), b TMEM175 p.Q65P (rs34884217), c SCARB2 rs6812193, d SCARB2 rs6825004, and e CTSB rs1293298. P values were corrected for multiple testing across ten ancestries and five genetic variants using the Benjamini–Hochberg method to control the false discovery rate. Abbreviations: AAC African American, AFR African, AJ Ashkenazi Jewish, AMR Latino and indigenous Americas, CAS Central Asian, EAS East Asian, EUR European, MDE Middle Eastern, SAS South Asian, CAH Complex Admixture History.

Fig. 2

General overview of analysis.