Proteogenomic links to human metabolic diseases

Abstract Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify disease causing genes and proteins and to improve our understanding of the underlying mechanisms. Here, we conducted a cis -focused proteogenomic analysis of 2,923 plasma proteins measured in 1,180 individuals using novel antibody-based assays (Olink® Explore 1536 and Explore Expansion) to identify disease causing genes and proteins across the human phenome. We describe 1,553 distinct credible sets of protein quantitative trait loci (pQTL), of which 256 contained cis-pQTLs not previously reported. We identify 224 cis-pQTLs shared with 578 unique health outcomes using statistical colocalization, including, gastrin releasing peptide (GRP) as a potential therapeutic target for type 2 diabetes. We observed convergence of phenotypic consequences of cis-pQTLs and rare loss-of-function gene burden for twelve protein coding genes (e.g., TIMD4 and low-density lipoprotein metabolism), highlighting the complementary nature of both approaches for drug target prioritization. Proteogenomic evidence also improved causal gene assignment at 40% (n=192) of overlapping GWAS loci, including DKKL1 as the candidate causal gene for multiple sclerosis. Our findings demonstrate the ability of broad capture, high-throughput proteomic technologies to robustly identify new gene-protein-disease links, provide mechanistic insight, and add value to existing GWASs by enabling and refining causal gene assignment.