IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50718-x.html
   My bibliography  Save this article

Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease

Author

Listed:
  • Abolfazl Doostparast Torshizi

    (LLC)

  • Dongnhu T. Truong

    (LLC)

  • Liping Hou

    (LLC)

  • Bart Smets

    (Janssen Pharmaceutica NV)

  • Christopher D. Whelan

    (LLC)

  • Shuwei Li

    (LLC)

Abstract

Parkinson’s disease is highly heterogeneous across disease symptoms, clinical manifestations and progression trajectories, hampering the identification of therapeutic targets. Despite knowledge gleaned from genetics analysis, dysregulated proteome mechanisms stemming from genetic aberrations remain underexplored. In this study, we develop a three-phase system-level proteogenomic analytical framework to characterize disease-associated proteins and dysregulated mechanisms. Proteogenomic analysis identified 577 proteins that enrich for Parkinson’s disease-related pathways, such as cytokine receptor interactions and lysosomal function. Converging lines of evidence identified nine proteins, including LGALS3, CSNK2A1, SMPD3, STX4, APOA2, PAFAH1B3, LDLR, HSPB1, BRK1, with potential roles in disease pathogenesis. This study leverages the largest population-scale proteomics dataset, the UK Biobank Pharma Proteomics Project, to characterize genetically-driven protein disturbances associated with Parkinson’s disease. Taken together, our work contributes to better understanding of genome-proteome dynamics in Parkinson’s disease and sets a paradigm to identify potential indirect mediators connected to GWAS signals for complex neurodegenerative disorders.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50718-x
    DOI: 10.1038/s41467-024-50718-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50718-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-50718-x?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. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    2. Catherine S. Storm & Demis A. Kia & Mona M. Almramhi & Sara Bandres-Ciga & Chris Finan & Aroon D. Hingorani & Nicholas W. Wood, 2021. "Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Amand F. Schmidt & Chris Finan & Maria Gordillo-Marañón & Folkert W. Asselbergs & Daniel F. Freitag & Riyaz S. Patel & Benoît Tyl & Sandesh Chopade & Rupert Faraway & Magdalena Zwierzyna & Aroon D. Hi, 2020. "Genetic drug target validation using Mendelian randomisation," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    4. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    5. 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.
    6. Clint L. Miller & Milos Pjanic & Ting Wang & Trieu Nguyen & Ariella Cohain & Jonathan D. Lee & Ljubica Perisic & Ulf Hedin & Ramendra K. Kundu & Deshna Majmudar & Juyong B. Kim & Oliver Wang & Christe, 2016. "Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci," Nature Communications, Nature, vol. 7(1), pages 1-16, November.
    7. Katerina Trajanoska & Claude Bhérer & Daniel Taliun & Sirui Zhou & J. Brent Richards & Vincent Mooser, 2023. "From target discovery to clinical drug development with human genetics," Nature, Nature, vol. 620(7975), pages 737-745, August.
    8. Gibran Hemani & Kate Tilling & George Davey Smith, 2017. "Orienting the causal relationship between imprecisely measured traits using GWAS summary data," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-22, November.
    9. Jian Jing Siew & Hui-Mei Chen & Huan-Yuan Chen & Hung-Lin Chen & Chiung-Mei Chen & Bing-Wen Soong & Yih-Ru Wu & Ching-Pang Chang & Yi-Chen Chan & Chun-Hung Lin & Fu-Tong Liu & Yijuang Chern, 2019. "Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    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. 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. Lucas A. Mavromatis & Daniel B. Rosoff & Andrew S. Bell & Jeesun Jung & Josephin Wagner & Falk W. Lohoff, 2023. "Multi-omic underpinnings of epigenetic aging and human longevity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Anders Mälarstig & Felix Grassmann & Leo Dahl & Marios Dimitriou & Dianna McLeod & Marike Gabrielson & Karl Smith-Byrne & Cecilia E. Thomas & Tzu-Hsuan Huang & Simon K. G. Forsberg & Per Eriksson & Mi, 2023. "Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    3. Eeva Sliz & Jaakko S. Tyrmi & Nilufer Rahmioglu & Krina T. Zondervan & Christian M. Becker & Outi Uimari & Johannes Kettunen, 2023. "Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. 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.
    5. Zhaotong Lin & Wei Pan, 2024. "A robust cis-Mendelian randomization method with application to drug target discovery," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. 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.
    7. 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.
    8. 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.
    9. Xiao-Yu He & Bang-Sheng Wu & Liu Yang & Yu Guo & Yue-Ting Deng & Ze-Yu Li & Chen-Jie Fei & Wei-Shi Liu & Yi-Jun Ge & Jujiao Kang & Jianfeng Feng & Wei Cheng & Qiang Dong & Jin-Tai Yu, 2024. "Genetic associations of protein-coding variants in venous thromboembolism," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    10. Lucia Trastulla & Georgii Dolgalev & Sylvain Moser & Laura T. Jiménez-Barrón & Till F. M. Andlauer & Moritz Scheidt & Monika Budde & Urs Heilbronner & Sergi Papiol & Alexander Teumer & Georg Homuth & , 2024. "Distinct genetic liability profiles define clinically relevant patient strata across common diseases," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    11. Javier Botey-Bataller & Hedwig D. Vrijmoeth & Jeanine Ursinus & Bart-Jan Kullberg & Cees C. Wijngaard & Hadewych Hofstede & Ahmed Alaswad & Manoj K. Gupta & Lennart M. Roesner & Jochen Huehn & Thomas , 2024. "A comprehensive genetic map of cytokine responses in Lyme borreliosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    12. Benjamin B. Sun & Stephanie J. Loomis & Fabrizio Pizzagalli & Natalia Shatokhina & Jodie N. Painter & Christopher N. Foley & Megan E. Jensen & Donald G. McLaren & Sai Spandana Chintapalli & Alyssa H. , 2022. "Genetic map of regional sulcal morphology in the human brain from UK biobank data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    13. Dmitrii Usoltsev & Nikita Kolosov & Oxana Rotar & Alexander Loboda & Maria Boyarinova & Ekaterina Moguchaya & Ekaterina Kolesova & Anastasia Erina & Kristina Tolkunova & Valeriia Rezapova & Ivan Molot, 2024. "Complex trait susceptibilities and population diversity in a sample of 4,145 Russians," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    14. Eamon Fitzgerald & Mojun Shen & Hannah Ee Juen Yong & Zihan Wang & Irina Pokhvisneva & Sachin Patel & Nicholas O’Toole & Shiao-Yng Chan & Yap Seng Chong & Helen Chen & Peter D. Gluckman & Jerry Chan &, 2023. "Hofbauer cell function in the term placenta associates with adult cardiovascular and depressive outcomes," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    15. Hui Chen & Zeyang Wang & Lihai Gong & Qixuan Wang & Wenyan Chen & Jia Wang & Xuelian Ma & Ruofan Ding & Xing Li & Xudong Zou & Mireya Plass & Cheng Lian & Ting Ni & Gong-Hong Wei & Wei Li & Lin Deng &, 2024. "A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    16. Yaohua Yang & Yaxin Chen & Shuai Xu & Xingyi Guo & Guochong Jia & Jie Ping & Xiang Shu & Tianying Zhao & Fangcheng Yuan & Gang Wang & Yufang Xie & Hang Ci & Hongmo Liu & Yawen Qi & Yongjun Liu & Dan L, 2024. "Integrating muti-omics data to identify tissue-specific DNA methylation biomarkers for cancer risk," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    17. William R. Reay & Michael P. Geaghan & Murray J. Cairns, 2022. "The genetic architecture of pneumonia susceptibility implicates mucin biology and a relationship with psychiatric illness," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Marie C. Sadler & Chiara Auwerx & Kaido Lepik & Eleonora Porcu & Zoltán Kutalik, 2022. "Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    19. Sylvia Hartmann & Summaira Yasmeen & Benjamin M. Jacobs & Spiros Denaxas & Munir Pirmohamed & Eric R. Gamazon & Mark J. Caulfield & Harry Hemingway & Maik Pietzner & Claudia Langenberg, 2023. "ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    20. Yuandan Wei & Jianxin Zhen & Liang Hu & Yuqin Gu & Yanhong Liu & Xinxin Guo & Zijing Yang & Hao Zheng & Shiyao Cheng & Fengxiang Wei & Likuan Xiong & Siyang Liu, 2024. "Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies," Nature Communications, Nature, vol. 15(1), pages 1-17, 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:15:y:2024:i:1:d:10.1038_s41467-024-50718-x. 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.