Integration of Brain Proteomes and Genome-Wide Association Data Identifies GLO1 as a Candidate Causal Gene and Therapeutic Target for Restless Legs Syndrome

Restless legs syndrome (RLS) is a common sensorimotor disorder with limited treatment options and incompletely understood pathophysiology. Genome-wide association studies have identified numerous risk loci, but translating these findings into causal genes and therapeutic targets remains challenging. We performed a proteome-wide association study (PWAS) integrating RLS genome-wide association study (GWAS) data from FinnGen with two brain pQTL datasets (ROSMAP and Banner). We validated the identified proteins using TWAS, SMR, and colocalization analyses using brain pQTL and eQTL datasets. To further investigate peripheral protein associations, we performed SMR using plasma pQTL data from the UK Biobank Pharma Proteomics Project (UKB-PPP). We also conducted a phenome-wide association study (PheWAS) to screen for potential off-target effects of the prioritized genes, followed by drug prediction using DSigDB and molecular docking. PWAS identified GLO1, along with GRWD1 and MAP2K5, as significantly associated with RLS. GLO1 was identified by brain-based SMR (p = 0.0001), colocalization (PP.H4 = 0.96), TWAS (p = 0.048), and was confirmed by plasma-based SMR (p = 3.16 × 10−9) as the only protein associated with RLS. PheWAS analysis, without associations for 783 non-RLS phenotypes, confirmed the specificity of GLO1. Among 27 predicted GLO1-targeting compounds, Gambierol had the strongest binding affinity (−8.3 kcal/mol). This proteogenomic study identifies GLO1 as a prioritized causal gene and promising drug target for RLS, combining brain and plasma data to provide new insights into pathogenesis and candidate drug development.