Blood protein levels predict leading incident diseases and mortality in UK Biobank

The circulating proteome offers insights into the biological pathways that underlie disease. Here, we test relationships between 1,468 Olink protein levels and the incidence of 23 age-related diseases and mortality, over 16 years of electronic health linkage in the UK Biobank (N=47,600). We report 3,201 associations between 961 protein levels and 21 incident outcomes, identifying proteomic indicators of multiple morbidities. Next, protein-based scores (ProteinScores) are developed using penalised Cox regression. When applied to test sets, six ProteinScores improve Area Under the Curve (AUC) estimates for the 10-year onset of incident outcomes beyond age, sex and a comprehensive set of 24 lifestyle factors, clinically-relevant biomarkers and physical measures. Furthermore, the ProteinScore for type 2 diabetes outperformed a polygenic risk score, a metabolomic score and HbA1c – a clinical marker used to monitor and diagnose type 2 diabetes. These data characterise early proteomic contributions to major age-related disease and demonstrate the value of the plasma proteome for risk stratification. ### Competing Interest Statement B.B.S., R.A., J.G., T.L., K.F., and H.R., are employed by Biogen. C.N.F., Z.K., D.A.G., M.D., and T.M., are employed by Optima partners. D.A.G., R.F.H., and R.E.M., have received consultancy fees from Optima Partners. R.E.M. is an advisor to the Epigenetic Clock Development Foundation. R.F.H., has received consultant fees from Illumina. All other authors declare no competing interests. ### Funding Statement This research was funded in whole, or in part, by the Wellcome Trust [108890/Z/15/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. We thank the participants, contributors, and researchers of UK Biobank for making data available for this study with special thanks to Lauren Carson, John Busby, Naomi Allen and Rory Collins for making the study possible. We are grateful to the research & development leadership teams at the thirteen participating UKB-PPP member companies (Alnylam Pharmaceuticals, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Calico, Genentech, Glaxo Smith Klein, Janssen Pharmaceuticals, Novo Nordisk, Pfizer, Regeneron, and Takeda) for funding the study. We thank the Legal and Business Development teams at each company for overseeing the contracting of this complex, precompetitive collaboration with particular thanks to Erica Olson of Amgen, Andrew Walsh of GSK, and Fiona Middleton of AstraZeneca. The Biogen team is especially thankful to Helen McLaughlin for her project management support. Finally, we thank the team at Olink Proteomics (Philippa Pettingell, Klev Diamanti, Cindy Lawley, Linda Jung, Sara Ghalib, Ida Grundberg and Jon Heimer) for their consistent logistic support throughout the project with special thanks to Evan Mills for co championing the project and leading internal activities at Olink. R.E.M. is supported by Alzheimers Society major project grant AS-PG-19b-010. R.F.H is supported by a MRC IEU Fellowship. D.A.G. is supported by the Wellcome Trust Translational Neuroscience programme [108890/Z/15/Z]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants provided informed consent. This research has been conducted using the UK Biobank Resource under approved application numbers 65851, 20361, 26041, 44257, 53639, 69804. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Datasets generated in this study are made available in Supplementary Tables . Proteomics data is available in the UK Biobank under Category 1838 at: .