Plasma proteomic associations with genetics and health in the UK Biobank.

Humans ABO Blood-Group System / genetics Biological Specimen Banks Blood Proteins / analysis COVID-19 / genetics Databases, Factual Drug Discovery Epistasis, Genetic Fucosyltransferases / metabolism Genetic Predisposition to Disease Genomics Health Plasma / chemistry Proprotein Convertase 9 / metabolism Proteome / analysis Proteomics Public-Private Sector Partnerships Quantitative Trait Loci United Kingdom Galactoside 2-alpha-L-fucosyltransferase

Journal

Nature

ISSN: 1476-4687

Titre abrégé: Nature

Pays: England

ID NLM: 0410462

Informations de publication

Date de publication:
Oct 2023

Historique:

received: 17 06 2022

accepted: 31 08 2023

medline: 23 10 2023

pubmed: 5 10 2023

entrez: 4 10 2023

Statut: ppublish

Résumé

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

Identifiants

DOI: 10.1038/s41586-023-06592-6 PMID: 37794186 PMC: PMC10567551

pubmed: 37794186

doi: 10.1038/s41586-023-06592-6

pii: 10.1038/s41586-023-06592-6

pmc: PMC10567551

doi:

Substances chimiques

ABO Blood-Group System 0

Blood Proteins 0

Fucosyltransferases EC 2.4.1.-

PCSK9 protein, human EC 3.4.21.-

Proprotein Convertase 9 EC 3.4.21.-

Proteome 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

329-338

Investigateurs

Hyun Ming Kang (HM)

Informations de copyright

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