RT Journal Article
SR Electronic
T1 Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.17.496443
DO 10.1101/2022.06.17.496443
A1 Benjamin B. Sun
A1 Joshua Chiou
A1 Matthew Traylor
A1 Christian Benner
A1 Yi-Hsiang Hsu
A1 Tom G. Richardson
A1 Praveen Surendran
A1 Anubha Mahajan
A1 Chloe Robins
A1 Steven G. Vasquez-Grinnell
A1 Liping Hou
A1 Erika M. Kvikstad
A1 Oliver S. Burren
A1 Madeleine Cule
A1 Jonathan Davitte
A1 Kyle L. Ferber
A1 Christopher E. Gillies
A1 Åsa K. Hedman
A1 Sile Hu
A1 Tinchi Lin
A1 Rajesh Mikkilineni
A1 Rion K. Pendergrass
A1 Corran Pickering
A1 Bram Prins
A1 Anil Raj
A1 Jamie Robinson
A1 Anurag Sethi
A1 Lucas D. Ward
A1 Samantha Welsh
A1 Carissa M. Willis
A1 Alnylam Human Genetics
A1 AstraZeneca Genomics Initiative
A1 Biogen Biobank Team
A1 Bristol Myers Squibb
A1 Genentech Human Genetics
A1 GlaxoSmithKline Genomic Sciences
A1 Pfizer Integrative Biology
A1 Population Analytics of Janssen Data Sciences
A1 Regeneron Genetics Center
A1 Lucy Burkitt-Gray
A1 Mary Helen Black
A1 Eric B. Fauman
A1 Joanna M. M. Howson
A1 Hyun Min Kang
A1 Mark I. McCarthy
A1 Eugene Melamud
A1 Paul Nioi
A1 Slavé Petrovski
A1 Robert A. Scott
A1 Erin N. Smith
A1 Sándor Szalma
A1 Dawn M. Waterworth
A1 Lyndon J. Mitnaul
A1 Joseph D. Szustakowski
A1 Bradford W. Gibson
A1 Melissa R. Miller
A1 Christopher D. Whelan
YR 2022
UL http://biorxiv.org/content/early/2022/06/18/2022.06.17.496443.abstract
AB 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 StatementThe 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.