IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56695-z.html
   My bibliography  Save this article

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities

Author

Listed:
  • Douglas P. Loesch

    (AstraZeneca)

  • Manik Garg

    (AstraZeneca)

  • Dorota Matelska

    (AstraZeneca)

  • Dimitrios Vitsios

    (AstraZeneca)

  • Xiao Jiang

    (AstraZeneca)

  • Scott C. Ritchie

    (University of Cambridge
    University of Cambridge
    University of Cambridge
    Wellcome Genome Campus and University of Cambridge)

  • Benjamin B. Sun

    (Biogen Inc.)

  • Heiko Runz

    (Biogen Inc.)

  • Christopher D. Whelan

    (Janssen Pharmaceuticals)

  • Rury R. Holman

    (University of Oxford)

  • Robert J. Mentz

    (Duke University School of Medicine)

  • Filipe A. Moura

    (Brigham and Women’s Hospital and Harvard Medical School
    Yale School of Medicine
    VA Connecticut Healthcare System)

  • Stephen D. Wiviott

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Marc S. Sabatine

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Miriam S. Udler

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Cambridge
    Harvard Medical School)

  • Ingrid A. Gause-Nilsson

    (AstraZeneca)

  • Slavé Petrovski

    (AstraZeneca)

  • Jan Oscarsson

    (AstraZeneca)

  • Abhishek Nag

    (AstraZeneca)

  • Dirk S. Paul

    (AstraZeneca
    AstraZeneca)

  • Michael Inouye

    (University of Cambridge
    University of Cambridge
    University of Cambridge
    Wellcome Genome Campus and University of Cambridge)

Abstract

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal ( https://public.cgr.astrazeneca.com/t2d-pgs/v1/ ).

Suggested Citation

  • Douglas P. Loesch & Manik Garg & Dorota Matelska & Dimitrios Vitsios & Xiao Jiang & Scott C. Ritchie & Benjamin B. Sun & Heiko Runz & Christopher D. Whelan & Rury R. Holman & Robert J. Mentz & Filipe , 2025. "Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56695-z
    DOI: 10.1038/s41467-025-56695-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56695-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56695-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Tian Ge & Chia-Yen Chen & Yang Ni & Yen-Chen Anne Feng & Jordan W. Smoller, 2019. "Polygenic prediction via Bayesian regression and continuous shrinkage priors," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Chris Wallace, 2021. "A more accurate method for colocalisation analysis allowing for multiple causal variants," PLOS Genetics, Public Library of Science, vol. 17(9), pages 1-11, September.
    3. Adam E. Locke & Bratati Kahali & Sonja I. Berndt & Anne E. Justice & Tune H. Pers & Felix R. Day & Corey Powell & Sailaja Vedantam & Martin L. Buchkovich & Jian Yang & Damien C. Croteau-Chonka & Tonu , 2015. "Genetic studies of body mass index yield new insights for obesity biology," Nature, Nature, vol. 518(7538), pages 197-206, February.
    4. Ryan S. Dhindsa & Oliver S. Burren & Benjamin B. Sun & Bram P. Prins & Dorota Matelska & Eleanor Wheeler & Jonathan Mitchell & Erin Oerton & Ventzislava A. Hristova & Katherine R. Smith & Keren Carss , 2023. "Rare variant associations with plasma protein levels in the UK Biobank," Nature, Nature, vol. 622(7982), pages 339-347, October.
    5. Grimur Hjorleifsson Eldjarn & Egil Ferkingstad & Sigrun H. Lund & Hannes Helgason & Olafur Th. Magnusson & Kristbjorg Gunnarsdottir & Thorunn A. Olafsdottir & Bjarni V. Halldorsson & Pall I. Olason & , 2023. "Large-scale plasma proteomics comparisons through genetics and disease associations," Nature, Nature, vol. 622(7982), pages 348-358, October.
    6. Quanli Wang & Ryan S. Dhindsa & Keren Carss & Andrew R. Harper & Abhishek Nag & Ioanna Tachmazidou & Dimitrios Vitsios & Sri V. V. Deevi & Alex Mackay & Daniel Muthas & Michael Hühn & Susan Monkley & , 2021. "Rare variant contribution to human disease in 281,104 UK Biobank exomes," Nature, Nature, vol. 597(7877), pages 527-532, September.
    7. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    8. Verena Zuber & Johanna Maria Colijn & Caroline Klaver & Stephen Burgess, 2020. "Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    9. Tingley, Dustin & Yamamoto, Teppei & Hirose, Kentaro & Keele, Luke & Imai, Kosuke, 2014. "mediation: R Package for Causal Mediation Analysis," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 59(i05).
    10. Benjamin B. Sun & Joshua Chiou & Matthew Traylor & Christian Benner & Yi-Hsiang Hsu & Tom G. Richardson & Praveen Surendran & Anubha Mahajan & Chloe Robins & Steven G. Vasquez-Grinnell & Liping Hou & , 2023. "Plasma proteomic associations with genetics and health in the UK Biobank," Nature, Nature, vol. 622(7982), pages 329-338, October.
    11. Danielle Rasooly & Gina M. Peloso & Alexandre C. Pereira & Hesam Dashti & Claudia Giambartolomei & Eleanor Wheeler & Nay Aung & Brian R. Ferolito & Maik Pietzner & Eric H. Farber-Eger & Quinn Stanton , 2023. "Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. Ken Suzuki & Konstantinos Hatzikotoulas & Lorraine Southam & Henry J. Taylor & Xianyong Yin & Kim M. Lorenz & Ravi Mandla & Alicia Huerta-Chagoya & Giorgio E. M. Melloni & Stavroula Kanoni & Nigel W. , 2024. "Genetic drivers of heterogeneity in type 2 diabetes pathophysiology," Nature, Nature, vol. 627(8003), pages 347-357, March.
    13. Mitja I. Kurki & Juha Karjalainen & Priit Palta & Timo P. Sipilä & Kati Kristiansson & Kati M. Donner & Mary P. Reeve & Hannele Laivuori & Mervi Aavikko & Mari A. Kaunisto & Anu Loukola & Elisa Lahtel, 2023. "FinnGen provides genetic insights from a well-phenotyped isolated population," Nature, Nature, vol. 613(7944), pages 508-518, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Alexander T. Williams & Jing Chen & Kayesha Coley & Chiara Batini & Abril Izquierdo & Richard Packer & Erik Abner & Stavroula Kanoni & David J. Shepherd & Robert C. Free & Edward J. Hollox & Nigel J. , 2023. "Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Yash Patel & Jean Shin & Eeva Sliz & Ariana Tang & Aniket Mishra & Rui Xia & Edith Hofer & Hema Sekhar Reddy Rajula & Ruiqi Wang & Frauke Beyer & Katrin Horn & Max Riedl & Jing Yu & Henry Völzke & Rob, 2024. "Genetic risk factors underlying white matter hyperintensities and cortical atrophy," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Jonathan Mitchell & Niedzica Camacho & Patrick Shea & Konrad H. Stopsack & Vijai Joseph & Oliver S. Burren & Ryan S. Dhindsa & Abhishek Nag & Jacob E. Berchuck & Amanda O’Neill & Ali Abbasi & Anthony , 2025. "Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    6. Abolfazl Doostparast Torshizi & Dongnhu T. Truong & Liping Hou & Bart Smets & Christopher D. Whelan & Shuwei Li, 2024. "Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Andras Gezsi & Sandra Auwera & Hannu Mäkinen & Nora Eszlari & Gabor Hullam & Tamas Nagy & Sarah Bonk & Rubèn González-Colom & Xenia Gonda & Linda Garvert & Teemu Paajanen & Zsofia Gal & Kevin Kirchner, 2024. "Unique genetic and risk-factor profiles in clusters of major depressive disorder-related multimorbidity trajectories," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Caitlin E. Carey & Rebecca Shafee & Robbee Wedow & Amanda Elliott & Duncan S. Palmer & John Compitello & Masahiro Kanai & Liam Abbott & Patrick Schultz & Konrad J. Karczewski & Samuel C. Bryant & Caro, 2024. "Principled distillation of UK Biobank phenotype data reveals underlying structure in human variation," Nature Human Behaviour, Nature, vol. 8(8), pages 1599-1615, August.
    9. Chirag Krishna & Joshua Chiou & Saori Sakaue & Joyce B. Kang & Stephen M. Christensen & Isac Lee & Melis Atalar Aksit & Hye In Kim & David Schack & Soumya Raychaudhuri & Daniel Ziemek & Xinli Hu, 2024. "The influence of HLA genetic variation on plasma protein expression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. Bingxin Zhao & Yujue Li & Zirui Fan & Zhenyi Wu & Juan Shu & Xiaochen Yang & Yilin Yang & Xifeng Wang & Bingxuan Li & Xiyao Wang & Carlos Copana & Yue Yang & Jinjie Lin & Yun Li & Jason L. Stein & Joa, 2024. "Eye-brain connections revealed by multimodal retinal and brain imaging genetics," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    11. Chamlee Cho & Beomsu Kim & Dan Say Kim & Mi Yeong Hwang & Injeong Shim & Minku Song & Yeong Chan Lee & Sang-Hyuk Jung & Sung Kweon Cho & Woong-Yang Park & Woojae Myung & Bong-Jo Kim & Ron Do & Hyon K., 2024. "Large-scale cross-ancestry genome-wide meta-analysis of serum urate," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Sang‑Hyuk Jung & Haemin Kim & Young Mi Jung & Manu Shivakumar & Brenda Xiao & Jaeyoung Kim & Beomjin Jang & Jae-Seung Yun & Hong-Hee Won & Chan-Wook Park & Joong Shin Park & Jong Kwan Jun & Dokyoon Ki, 2025. "Healthy lifestyle reduces cardiovascular risk in women with genetic predisposition to hypertensive disorders of pregnancy," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    13. Gudmundur Einarsson & Gudmar Thorleifsson & Valgerdur Steinthorsdottir & Florian Zink & Hannes Helgason & Thorhildur Olafsdottir & Solvi Rognvaldsson & Vinicius Tragante & Magnus O. Ulfarsson & Gardar, 2024. "Sequence variants associated with BMI affect disease risk through BMI itself," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    14. Jujiao Kang & Yue-Ting Deng & Bang-Sheng Wu & Wei-Shi Liu & Ze-Yu Li & Shitong Xiang & Liu Yang & Jia You & Xiaohong Gong & Tianye Jia & Jin-Tai Yu & Wei Cheng & Jianfeng Feng, 2024. "Whole exome sequencing analysis identifies genes for alcohol consumption," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    15. Baihan Wang & Alfred Pozarickij & Mohsen Mazidi & Neil Wright & Pang Yao & Saredo Said & Andri Iona & Christiana Kartsonaki & Hannah Fry & Kuang Lin & Yiping Chen & Huaidong Du & Daniel Avery & Dan Sc, 2025. "Comparative studies of 2168 plasma proteins measured by two affinity-based platforms in 4000 Chinese adults," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    16. Xingjie Hao & Zhonghe Shao & Ning Zhang & Minghui Jiang & Xi Cao & Si Li & Yunlong Guan & Chaolong Wang, 2023. "Integrative genome-wide analyses identify novel loci associated with kidney stones and provide insights into its genetic architecture," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    17. Mihail Halachev & Viktoria-Eleni Gountouna & Alison Meynert & Gannie Tzoneva & Alan R. Shuldiner & Colin A. Semple & James F. Wilson, 2024. "Regionally enriched rare deleterious exonic variants in the UK and Ireland," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    18. Shiyu Zhang & Zheng Wang & Yijing Wang & Yixiao Zhu & Qiao Zhou & Xingxing Jian & Guihu Zhao & Jian Qiu & Kun Xia & Beisha Tang & Julian Mutz & Jinchen Li & Bin Li, 2024. "A metabolomic profile of biological aging in 250,341 individuals from the UK Biobank," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    19. Magdalena Zimoń & Yunfeng Huang & Anthi Trasta & Aliaksandr Halavatyi & Jimmy Z. Liu & Chia-Yen Chen & Peter Blattmann & Bernd Klaus & Christopher D. Whelan & David Sexton & Sally John & Wolfgang Hube, 2021. "Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    20. Rikifumi Ohta & Yosuke Tanigawa & Yuta Suzuki & Manolis Kellis & Shinichi Morishita, 2024. "A polygenic score method boosted by non-additive models," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56695-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.