Proteomic and genetic insights into ancestry-specific associations in Parkinson’s disease

Genome-wide association studies of Parkinson’s disease (PD) have identified multiple genetic variants across populations, but the biological mechanisms remain largely unknown. To investigate ancestry-specific disease pathways, we performed a series of Mendelian randomisation analyses, integrating GWAS results with ancestry-specific protein quantitative trait loci data. For Europeans, we utilised the UK Biobank plasma proteomics (UKB-PPP) dataset alongside a European PD GWAS. For East Asians, we combined plasma proteomic data from Han Chinese and the East Asian subset of UKB-PPP with an East Asian PD GWAS. We identified 21 protein-encoding genes causally associated with PD in Europeans and 8 in East Asians, with BST1 common to both (Europeans: OR=1.04, 95% CI 1.02-1.06; East Asians: OR=1.18, 95% CI 1.10-1.27). Ancestry-specific associations included PRSS53 and TXNDC15 in Europeans, and HDGF , PM20D1 , and TOP1 in East Asians. These findings highlighted ancestry-related differences in gene-protein-PD associations and have implications for biomarker development and targeted therapeutic strategies.