Proteomic and Genetic Insights into Ancestry-Specific Associations in Parkinson's Disease.

BACKGROUND

Although genome-wide association studies (GWAS) have identified numerous common genetic risk variants for Parkinson's disease (PD), the underlying biological mechanisms remain largely unresolved.

OBJECTIVES

We aimed to identify circulating proteins causally associated with PD risk in European and East Asian populations and determine whether these associations are shared or ancestry-specific.

METHODS

We employed a two-sample Mendelian randomization (MR) approach, integrating large-scale proteomic and genetic data, with validation using summary-data-based MR (SMR). European analyses used UK Biobank Pharma Proteomics Project (UKB-PPP; n = 54,219; 2,392 proteins) and a large PD GWAS (37,688 cases, 18,618 proxy cases, 1.4 million controls). East Asian analyses combined Han Chinese and UKB-PPP data (n = 3,220; 229 proteins) with a PD GWAS (6,724 cases, 24,851 controls). False discovery rate (FDR) < 0.05 determined significance. Sensitivity analyses addressed instrument heterogeneity, pleiotropy, and sample overlap.

RESULTS

MR analyses identified 21 proteins causally associated with PD in Europeans and 8 in East Asians, all directionally concordant in SMR validation. Notably, BST1 emerged as a shared causal protein, increasing PD risk in both Europeans (odds ratio [OR] = 1.04, 95% confidence interval [CI]: 1.02-1.06) and East Asians (OR = 1.18, 95% CI: 1.10-1.27), remaining robust after excluding UK Biobank participants. Several ancestry-specific proteins were detected, including TXNDC15 in Europeans and PM20D1 in East Asians, both targets of existing or investigational drugs.

CONCLUSIONS

This cross-ancestry proteogenomic analysis reveals shared and ancestry-specific proteomic signatures causally linked to PD, underscoring the importance of using ancestry-aware analytical frameworks to discover robust biomarkers and novel therapeutic targets. © 2026 International Parkinson and Movement Disorder Society.