Sex-biased Genetic Risk Loci and Causal Brain Proteins in Parkinson’s Disease
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Parkinson’s disease (PD) exhibits pronounced sex differences, yet the underlying genetic and molecular mechanisms remain poorly understood. We performed the largest-to-date meta-analysis of sex-stratified genome-wide association studies of PD followed by brain proteogenomics-based causal inference analyses. We nominated 10 candidate proteins that appear important to sex-biased PD risk, of which 2 female-biased, GALC and PSMG1, and 3 male-biased, ACTR1B, WDR41, and CD151, were most robustly prioritized. Together, our findings provide evidence for genetic sex differences in PD, prioritizing sex-biased proteins implicated in lysosomal regulation, neuroinflammation, lipid biology, and other PD-relevant mechanisms, and highlighting potential sex-informed therapeutic opportunities.
