Plasma proteomic associations with genetics and health in the UK Biobank

TLDR

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium that characterizes plasma proteomic profiles of 54,219 UK Biobank participants. The study aims to provide a comprehensive summary of the consortium’s work, including technical and biological validations, disease signature insights, and predictive modeling of demographic and health indicators. The authors detail the technical validation, biological validation, disease signature analyses, and predictive modeling approaches used in the initiative. They mapped 2,923 proteins to 14,287 primary pQTLs—81 % novel—along with ancestry‑specific associations, trans‑pQTL insights, ligand‑receptor and pathway perturbations, long‑range epistatic effects of ABO/FUT2, and drug‑discovery applications such as PCSK9, while also elucidating genes linked to COVID‑19 susceptibility, thereby offering an open‑access resource for biomarker and therapeutic development.

Abstract

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics