Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants
Author:
Sun Benjamin B.ORCID, Chiou JoshuaORCID, Traylor MatthewORCID, Benner ChristianORCID, Hsu Yi-HsiangORCID, Richardson Tom G.ORCID, Surendran PraveenORCID, Mahajan AnubhaORCID, Robins ChloeORCID, Vasquez-Grinnell Steven G.ORCID, Hou LipingORCID, Kvikstad Erika M.ORCID, Burren Oliver S.ORCID, Cule MadeleineORCID, Davitte JonathanORCID, Ferber Kyle L.ORCID, Gillies Christopher E.ORCID, Hedman Åsa K.ORCID, Hu SileORCID, Lin TinchiORCID, Mikkilineni RajeshORCID, Pendergrass Rion K.ORCID, Pickering CorranORCID, Prins BramORCID, Raj AnilORCID, Robinson JamieORCID, Sethi AnuragORCID, Ward Lucas D.ORCID, Welsh SamanthaORCID, Willis Carissa M.ORCID, Burkitt-Gray LucyORCID, Black Mary HelenORCID, Fauman Eric B.ORCID, Howson Joanna M. M.ORCID, Kang Hyun MinORCID, McCarthy Mark I.ORCID, Melamud EugeneORCID, Nioi PaulORCID, Petrovski SlavéORCID, Scott Robert A.ORCID, Smith Erin N.ORCID, Szalma SándorORCID, Waterworth Dawn M.ORCID, Mitnaul Lyndon J., Szustakowski Joseph D.ORCID, Gibson Bradford W.ORCID, Miller Melissa R.ORCID, Whelan Christopher D.ORCID, , , , , , , , ,
Abstract
AbstractThe 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
51 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|