Genome-Wide Association and Population-Tailored Polygenic Risk for Parkinson's Disease in Taiwan

Parkinsons disease genetics remain under-characterized in East Asians. We recruited a Taiwanese case-control cohort (2,245 PD; 2,147 controls), genotyped on the Illumina NeuroBooster Array, and imputed 7.6 million variants using the Taiwan Biobank reference. Logistic-regression GWAS identified genome-wide significant signals at SNCA and MCCC1; we also observed suggestive associations at GCH1, PPARGC1A and GALNT13. Haplotype analyses delineated an East Asian SNCA risk haplotype and confirmed effects at LRRK2 p.G2385R and p.Rorg8P. Moreover, we have discovered, for the first time, a gene dosage effect of LRRK2 Asian variants. A European-derived PRS (Nalls 2019) showed modest discrimination in our cohort (AUC 0.590); incorporating Asian and Taiwan-specific variants increased the AUC to 0.615 (DeLong p<0.001). Our data define the genetic architecture of PD in Taiwan, highlight both shared and population-specific risk, and demonstrate that tailoring polygenic risk scores to ancestry-specific genetic structure improves risk stratification.