Integrating dorsolateral prefrontal cortex multi-omics and GWAS summary data reveals genetic etiology of Parkinson's...

To better illustrate the genetic etiology of Parkinson's disease (PD), we integrated xQTL weights derived from bulk RNA-seq (n=931), single-nucleus RNA-seq (n=415), and bulk proteomics (n=716) data of dorsolateral prefrontal cortex (DLPFC) with the largest available GWAS summary data of PD. Through integrative Omnibus TWAS and PWAS analyses, we detected risk genes whose genetic effects are mediated through bulk or cell-type-aware gene expression, or bulk protein abundances in DLPFC. We detected 39 significant risk genes by bulk TWAS, 66 by cell-type-aware TWAS across six brain cell types, and 17 by bulk PWAS. Importantly, 57.9% bulk and 62.5% cell-type-aware independent TWAS risk genes are replicated by bulk PWAS. Protein-protein interaction analyses reveal strong connectivity of our detected risk genes with known PD risk genes such as MAPT, SNCA, and LRRC37A. Our detected TWAS and PWAS risk genes are shown enriched in apoptosis signaling and T-cell activation pathways.