Genetic risk loci for Parkinson's disease and dementia in a large-scale population-based Taiwanese cohort (TPMI)

BackgroundThe genetic architecture of Parkinson's disease (PD) and progression to PD dementia (PDD) remains incompletely characterized in Asians. Here, we investigated genetic risk factors for PD and PDD in Taiwanese individuals from the Taiwan Precision Medicine Initiative (TPMI), the largest non-European cohort integrating genetic and electronic medical record data.MethodsWe conducted a two-stage population-based case–control genome-wide association study (GWAS) with a 1:10 case-to-control ratio. Results were meta-analyzed with an independent Asian GWAS. We further constructed a polygenic risk score (PRS) to distinguish PD cases from controls. PDD risk was assessed using logistic regression and Cox models, with replication in an independent cohort that underwent whole-genome sequencing (WGS).FindingsAmong 463,447 TPMI participants, 4381 PD patients and 43,810 controls were analysed. We confirmed established PD loci at SNCA and LRRK2, and identified additional risk variants near HLA, AOAH–ELMO1, WFDC11–WFDC10B, TECPR1, BORCS7, and HIP1R. PRS models discriminated PD from controls with 70% accuracy. Among PD patients, 333 developed PDD. Genome-wide survival analysis identified PRDM15 rs141772267 as a novel PDD risk variant (HR = 4.20; 95% CI 2.67–6.60; P = 5.41 × 10−10), together with two loci near CNOT6L–MRPL1 and NPY2R–MAP9. Carriers of two or more minor risk alleles showed a markedly increased risk of progression to PDD (P = 2 × 10−16), which was replicated in an independent WGS cohort.InterpretationOur findings highlight both shared and ethnicity-specific PD risk loci and identify PRDM15 as a potential novel contributor to PDD. Further multi-ethnic and functional studies are warranted.FundingAcademia Sinica and National Development Fund.