Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants

The UK Biobank Pharma Proteomics Project (UKB-PPP) is a collaboration between the UK Biobank (UKB) and thirteen biopharmaceutical companies characterising the plasma proteomic profiles of 54,306 UKB participants. Here, we describe results from the first phase of UKB-PPP, including protein quantitative trait loci (pQTL) mapping of 1,463 proteins that identifies 10,248 primary genetic associations, of which 85% are newly discovered. We also identify independent secondary associations in 92% of cis and 29% of trans loci, expanding the catalogue of genetic instruments for downstream analyses. The study provides an updated characterisation of the genetic architecture of the plasma proteome, leveraging population-scale proteomics to provide novel, extensive insights into trans pQTLs across multiple biological domains. We highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement proteins, 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 target discovery by extending the genetic proxied effect of PCSK9 levels on lipid concentrations, cardio- and cerebro-vascular diseases, and additionally disentangle specific genes and proteins perturbed at COVID-19 susceptibility loci. This public-private partnership provides the scientific community with an open-access proteomics resource of unprecedented breadth and depth to help elucidate biological mechanisms underlying genetic discoveries and accelerate the development of novel biomarkers and therapeutics. ### Competing Interest Statement The authors declare the following competing interests: L.D.W, P.N., C.M.W. are employees and/or stockholders of Alnylam; Y.H.H., B.W.G. are employees and/or stockholders of Amgen; S.P., O.S.B., B.P. are employees and/or stockholders of AstraZeneca; B.B.S., C.D.W., T.L., K.L.F. are employees and/or stockholders of Biogen; E.M.K., J.D.K., S.V.G. are employees and/or stockholders of Bristol Myers Squibb; M.C. A.R., A.S., E.M. are employees and/or stockholders of Calico; R.K.P, M.I.M, A.M., C.B. are employees and/or stockholders of Genentech; C.R., P.S., R.A.S., J.D. are employees and/or stockholders of GlaxoSmithKline; M.H.B., L.H. D.M.. are employees and/or stockholders of Janssen Research & Development; T.G.R., J.M.H., S.H., M.T. are employees and/or stockholders of Novo Nordisk; A.K.H., E.B.F, J.C., M.R.M. are employees and/or stockholders of Pfizer; H.M.K., L.J.M., C.E.G. are employees and/or stockholders of Regeneron; E.N.S, S.S., R.M. are employees and/or stockholders of Takeda.