An Integrated Large-Scale Atlas of Protein Quantitative Trait Loci across Olink and SomaScan platforms.

Protein quantitative trait loci (pQTLs) provide insight into the genetic regulation of protein expression and disease biology. We performed a large-scale cross-platform meta-analysis of plasma proteomics, integrating data from over 90,000 individuals across Olink and SomaScan platforms. This effort identified >30,000 sentinel pQTLs, with multi-trait approach (MTAG) markedly boosting both discovery and replication, despite the potential differences in the protein measurements of the two platforms. While both platforms captured well-known pleiotropic loci ( HLA, ABO, SH2B3 ), we also uncovered platform-specific associations, reflecting unique assay designs. We further established a comprehensive resource for transcriptome- and proteome-wide association studies (TWAS, PWAS), identifying >100,000 upstream regulators with strong replication. As a proof of concept, we applied this framework to inflammatory bowel disease (IBD), generating the largest to date GWAS directly comparing Crohn's disease (CD) and ulcerative colitis (UC). Integrative multi-omics analyses revealed divergent loci enriched in the NF- κ B signaling pathway and improved CD vs. UC classification when proteomic features were combined with polygenic risk scores (PRS). Our findings provide a comprehensive resource for plasma protein genetics and demonstrate the value of integrative multi-omics for disease subtype classification, with broad implications for precision medicine.