Abstract
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.
Footnotes
↵# These authors jointly directed the work.
