Large-scale evaluation of proteomic and polygenic risk scores reveals complementary contributions to incident disease prediction

Abstract Plasma proteins capture dynamic physiological processes and may offer more immediate insight into disease risk than static genetic predictors. We evaluated the predictive utility of proteomic risk scores (ProRS) versus polygenic risk scores (PRS) across 301 phenotypes in 39,843 participants from the UK Biobank Pharma Proteomics Project. ProRS, trained on prevalent cases, were tested for incident disease and benchmarked against PRS derived from genome-wide association statistics. Among 268 phenotypes with informative signals, ProRS outperformed PRS in 88% of traits (a median C-index improvement of 9.6%), showing strongest gains for circulatory, metabolic, and immune conditions. Combined models further improved prediction, particularly for traits with higher heritability. Longitudinal analyses showed that ProRS values were elevated years before diagnosis. External validation in 841 Penn Medicine BioBank participants confirmed consistent performance and transferability, with AUC improvements up to 4.18% over PRS alone. Plasma proteomic profiling provides complementary, temporally responsive information that enhances individual-level disease prediction. Competing Interest Statement Dr. Gelfand served as a consultant for Abbvie, Artax (DSMB), BMS, Boehringer Ingelheim, Celldex (DSMB), FIDE (which is sponsored by multiple pharmaceutical companies) GSK, Inmagene (DSMB), Lilly, Leo, Moonlake (DSMB), Janssen Biologics, Novartis Corp, UCB (DSMB), Neuroderm (DSMB), Oruka, Inc, Teva (DSMB), and Veolia North America receiving honoraria; and receives research grants (to the Trustees of the University of Pennsylvania) from Amgen, BMS, and Pfizer Inc.; and received payment for continuing medical education work related to psoriasis that was supported indirectly pharmaceutical sponsors. Dr Gelfand is a Deputy Editor for the Journal of Investigative Dermatology receiving honoraria from the Society for Investigative Dermatology, is Chief Medical Editor for Healio Dermatology (receiving honoraria) and is a member of the Board of Directors for the International Psoriasis Council and the Medical Dermatology Society, receiving no honoraria. Funding Statement This work was supported by NIGMS R01 GM138597 and NHLBI R01 HL169458. M.G. Levin was supported by the Doris Duke Foundation (Award 2023-0224) and US Department of Veterans Affairs Biomedical Research and Development Award IK2-BX006551. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. M.G. Levin reports research grants from MyOme and consulting fees from BridgeBio, unrelated to the present work. M.A. Guerraty was supported by Burroughs Wellcome Fund and the Penn Cardiovascular Institute (MG). S.A. Apostolidis was supported by K08AR081929 and a Rheumatology Research Foundation Scientist Development Award. Use of the UK Biobank Resource in the current study was approved under Application Number [32133]. We thank all the participants and researchers of the UK Biobank and the FinnGen study. We acknowledge the Penn Medicine BioBank (PMBB) for providing data and thank the patient- participants of Penn Medicine who consented to participate in this research program. We would also like to thank the Penn Medicine BioBank team and Regeneron Genetics Center for providing genetic variant data for analysis. The PMBB is approved under IRB protocol# 813913 and supported by Perelman School of Medicine at University of Pennsylvania, a gift from the Smilow family, and the National Center for Advancing Translational Sciences of the National Institutes of Health under CTSA award number UL1TR001878. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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 Footnotes ↵* Y.N and D.K jointly supervised. Data Availability All data produced in the present study are available upon reasonable request to the authors.