Leveraging large-scale biobanks for therapeutic target discovery

Brian R Ferolito¹, Hesam Dashti², Claudia Giambartolomei³, Gina M Peloso⁴, Daniel J Golden⁵, Kai Gravel-Pucillo⁵, Danielle Rasooly⁵, Andrea R V R Horimoto⁵, Rachael Matty⁶, Liam Gaziano⁷, Yi Liu⁸, Ines A Smit⁹, Barbara Zdrazil⁹, Yakov Tsepilov¹⁰, Lauren Costa⁶, Nicole Kosik⁶, Jennifer E Huffman¹¹, Gian Gaetano Tartaglia¹², Giorgio Bini¹³, Gabriele Proietti¹⁴, Harris Ioannidis⁹, Mohd A Karim¹⁵, Fiona Hunter⁹, Gibran Hemani⁸, Adam S Butterworth¹⁶, Emanuele Di Angelantonio¹⁷, Claudia Langenberg¹⁸, Maya Ghoussaini¹⁹, Andrew R Leach²⁰, Katherine P Liao²¹, Scott Damrauer²², Luis E Selva²³, Stacey Whitbourne²⁴, Philip S Tsao²⁵, Jennifer Moser²⁶, Tom Gaunt⁸, Tianxi Cai²⁷, John C Whittaker²⁸; Million Veteran Program; Juan P Casas²⁹, Sumitra Muralidhar²⁶, J Michael Gaziano²⁴, Kelly Cho²⁴, Alexandre C Pereira²⁴

Affiliations

¹ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA. Electronic address: brian.ferolito@va.gov.
² Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
³ Health Data Science Centre, Human Technopole, V.le Rita Levi-Montalcini, 1, 20157 Milan, Italy; Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy.
⁴ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Department of Biostatistics, Boston University School of Public Health, Crosstown Center, 801 Massachusetts Avenue, Boston, MA 02115, USA.
⁵ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
⁶ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA.
⁷ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge CB2 0BB, UK.
⁸ MRC Integrative Epidemiology Unit, Bristol Medical School, Bristol BS8 1QU, UK.
⁹ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SD, UK.
¹⁰ Open Targets, Hinxton CB10 1SD, UK.
¹¹ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹² Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy; ICREA - Institució Catalana de Recerca i Estudis Avançats, Passeig Llúis Companys 23, 08010 Barcelona, Spain.
¹³ Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy; Università degli Studi di Genova, Via Balbi 5, 16126 Genova, Italy.
¹⁴ Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy.
¹⁵ Genomic Discovery, Variant Bio, Seattle, WA 98109, USA.
¹⁶ BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge CB2 0BB, UK; NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge CB2 0BB, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0BB, UK; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0BB, UK; Health Data Research UK Cambridge, Wellcome Genome Campus, and University of Cambridge, Cambridge CB2 0BB, UK.
¹⁷ Health Data Science Centre, Human Technopole, V.le Rita Levi-Montalcini, 1, 20157 Milan, Italy; BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge CB2 0BB, UK; NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge CB2 0BB, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0BB, UK; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0BB, UK; Health Data Research UK Cambridge, Wellcome Genome Campus, and University of Cambridge, Cambridge CB2 0BB, UK.
¹⁸ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK; Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin, Berlin, Germany; MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0SR, UK.
¹⁹ Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
²⁰ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SD, UK; Open Targets, Hinxton CB10 1SD, UK.
²¹ Medicine, Rheumatology, VA Boston Healthcare System, 150 S. Huntington, Boston, MA 02130, USA; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
²² Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
²³ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Radiology, Boston University, Chobanian and Avedisian School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
²⁴ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
²⁵ Palo Alto Veterans Institute for Research (PAVIR), VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA; Department of Medicine, Stanford University, Palo Alto, CA 94304, USA.
²⁶ Office of Research and Development, Department of Veterans Affairs, Washington, DC 20420, USA.
²⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
²⁸ MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK.
²⁹ Biomarker Development/Translational Medicine, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

PMID: 41376171
PMCID: PMC12799792
DOI: 10.1016/j.xhgg.2025.100556

Leveraging large-scale biobanks for therapeutic target discovery

Brian R Ferolito et al. HGG Adv. 2026.

. 2026 Jan 15;7(1):100556.

doi: 10.1016/j.xhgg.2025.100556. Epub 2025 Dec 9.

Authors

Affiliations

¹ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA. Electronic address: brian.ferolito@va.gov.
² Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
³ Health Data Science Centre, Human Technopole, V.le Rita Levi-Montalcini, 1, 20157 Milan, Italy; Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy.
⁴ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Department of Biostatistics, Boston University School of Public Health, Crosstown Center, 801 Massachusetts Avenue, Boston, MA 02115, USA.
⁵ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
⁶ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA.
⁷ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge CB2 0BB, UK.
⁸ MRC Integrative Epidemiology Unit, Bristol Medical School, Bristol BS8 1QU, UK.
⁹ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SD, UK.
¹⁰ Open Targets, Hinxton CB10 1SD, UK.
¹¹ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹² Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy; ICREA - Institució Catalana de Recerca i Estudis Avançats, Passeig Llúis Companys 23, 08010 Barcelona, Spain.
¹³ Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy; Università degli Studi di Genova, Via Balbi 5, 16126 Genova, Italy.
¹⁴ Centre for Human Technologies (CHT), Insituto Italiano di Tecnologia, Via Enrico Melen 83, Building B, 7th Floor, 16152 Genova, Italy.
¹⁵ Genomic Discovery, Variant Bio, Seattle, WA 98109, USA.
¹⁶ BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge CB2 0BB, UK; NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge CB2 0BB, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0BB, UK; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0BB, UK; Health Data Research UK Cambridge, Wellcome Genome Campus, and University of Cambridge, Cambridge CB2 0BB, UK.
¹⁷ Health Data Science Centre, Human Technopole, V.le Rita Levi-Montalcini, 1, 20157 Milan, Italy; BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge CB2 0BB, UK; NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge CB2 0BB, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0BB, UK; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0BB, UK; Health Data Research UK Cambridge, Wellcome Genome Campus, and University of Cambridge, Cambridge CB2 0BB, UK.
¹⁸ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK; Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin, Berlin, Germany; MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0SR, UK.
¹⁹ Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
²⁰ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SD, UK; Open Targets, Hinxton CB10 1SD, UK.
²¹ Medicine, Rheumatology, VA Boston Healthcare System, 150 S. Huntington, Boston, MA 02130, USA; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
²² Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
²³ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Radiology, Boston University, Chobanian and Avedisian School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
²⁴ Million Veteran Program (MVP) Coordinating Center, Veterans Affairs Healthcare System, 2 Avenue de Lafayette, Boston, MA 02111, USA; Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
²⁵ Palo Alto Veterans Institute for Research (PAVIR), VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA; Department of Medicine, Stanford University, Palo Alto, CA 94304, USA.
²⁶ Office of Research and Development, Department of Veterans Affairs, Washington, DC 20420, USA.
²⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
²⁸ MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK.
²⁹ Biomarker Development/Translational Medicine, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

PMID: 41376171
PMCID: PMC12799792
DOI: 10.1016/j.xhgg.2025.100556

Abstract

Large biobanks, including the Million Veteran Program (MVP), the UK Biobank, and FinnGen, provide genetic association results for more than 1 million individuals for hundreds of phenotypes. To select targets for pharmaceutical development, as well as to improve the understanding of existing targets, we harmonized these studies and performed two-sample Mendelian randomization (MR) on 2,003 phenotypes using genetic variants associated with gene expression (derived from GTEx and eQTLGen) and plasma protein levels (derived from ARIC, Fenland, and deCODE) as proxies of target modulation. We found 69,669 gene-trait pairs with evidence (p ≤ 1.6 × 10^-9) for causal effects. From the selected gene-trait pairs, we observed 6,447 genes with strong causal evidence for at least one of 2,003 investigated traits. As expected, being identified as a gene-trait pair in our approach was significantly associated with higher odds of being an approved drug target and indication. We were able to rediscover 9% of approved drug targets in ChEMBL 34. Moreover, identified gene-traits were significantly associated with higher odds of being previously described as a gene-trait pair in OMIM, ClinVar, mouse knockout data, and rare variant burden studies. To enhance the translational potential of the resource, we developed a predictive ranking model trained using approved drug targets described in ChEMBL 34 as well as several different biological annotations. This model was able to accurately predict the odds of a particular significant MR result being developed into an approved drug and its clinical indication (precision-recall area under the receiver operating characteristic curve 0.79). We make our results publicly available in CIPHER.

Keywords: Mendelian randomization; genomics; target identification.

Published by Elsevier Inc.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests A.S.B. reports grants outside of this work from AstraZeneca, Bayer, Biogen, BioMarin, and Sanofi. M.G. is a full-time employee of Regeneron Genetics Center; her main contributions occurred while she was an employee of Open Targets. J.P.C. is a full-time employee at Novartis Institutes for Biomedical Research; his main contributions to the project occurred while employed at the VA Boston Healthcare System. M.A.K. is a full-time employee at Variant Bio; his main contributions occurred while he was an employee of Open Targets.

Figures

**Figure 1**
A flowchart demonstrating the main findings from the pipeline and the resulting counts of both rediscovery and repurposing opportunities

**Figure 2**
Plots demonstrating the overlap ands odds ratios of orthogonal sources (A) Upset plot representing the different intersection numbers of gene-traits among the used sources of orthogonal biological information. (B) Forest plot of the association between the different biological features as predictors of being a significant MR gene-trait. Different distance metrics used for capturing a trait match were exact, same EFO term for both MVP and biological database; distant, closest 3% terms in the ranked list between MVP and biological database using a semantic distance metric; parent, same parent term in both MVP and biological database. Error bars represent 95% confidence intervals.

**Figure 3**
Results from genetic rediscoveries of approved drugs (A) Stacked bar plot of the distribution of parent terms for all currently approved drugs indications (left bar), and distribution of parent terms among gene-trait pairs considered rediscoveries (right bar). (B) Forest plot representing the over- or underrepresentation of specific parent terms among rediscoveries. The error bars represent 95% confidence intervals. (C) Mean number of available genetic phenotypes per parent term indication. (D) Mean number of cases used to calculate the association between genetic variants and the outcome per parent term.

**Figure 4**
Circle plot representing the flow of disease categories for approved drug indications to the disease categories of potential repurposing opportunities based upon our findings

**Figure 5**
Precision-recall estimate of our classifier

See this image and copyright information in PMC

References

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Leveraging large-scale biobanks for therapeutic target discovery

Affiliations

Leveraging large-scale biobanks for therapeutic target discovery

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

LinkOut - more resources

Full Text Sources

Research Materials

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