Parietal Cortex Transcriptomics Refines Parkinson Disease GWAS Nomination and Highlights STAT3 as a Putative Upstream Glial Regulator

Parkinson's disease (PD) impacts over 1.1 million people in the United States and approximately 12 million globally. While Genome Wide Association Studies (GWAS) have significantly improved our understanding of PD's genetic makeup, the mechanisms that connect PD risk loci to disease-related gene expression are not yet fully understood, making it challenging to infer disease mechanisms from genetic associations alone.

In this study, researchers combined disease-state parietal cortex transcriptomics with the International Parkinson Disease Genomics Consortium (iPDGC) locus prioritization to improve PD gene nomination and pinpoint genetic candidates that were overlooked by GWAS.

By analyzing bulk RNA-seq data from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, the researchers prioritized candidate genes across 78 loci. They then categorized these genes based on the alignment between genetic evidence and differential expression in diseased cortices. This integrative strategy uncovered genes not detected by external GWAS-based prioritization methods and emphasized synaptic, lysosomal, and proteostasis pathways as key elements of PD risk biology.

Further network and transcription factor analyses revealed that these genes are regulated cooperatively. Among them, STAT3 emerged as a potential upstream glial regulator. The findings suggest that combining disease-state transcriptomics with genetic prioritization can fine-tune PD risk-gene nomination and reveal regulatory pathways that may be missed by GWAS alone.