IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31707-4.html
   My bibliography  Save this article

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Author

Listed:
  • Anne Senabouth

    (Garvan Institute of Medical Research)

  • Maciej Daniszewski

    (The University of Melbourne
    Royal Victorian Eye and Ear Hospital)

  • Grace E. Lidgerwood

    (The University of Melbourne
    Royal Victorian Eye and Ear Hospital)

  • Helena H. Liang

    (Royal Victorian Eye and Ear Hospital)

  • Damián Hernández

    (The University of Melbourne
    Royal Victorian Eye and Ear Hospital)

  • Mehdi Mirzaei

    (Macquarie University)

  • Stacey N. Keenan

    (The University of Melbourne)

  • Ran Zhang

    (Garvan Institute of Medical Research)

  • Xikun Han

    (QIMR Berghofer Medical Research Institute)

  • Drew Neavin

    (Garvan Institute of Medical Research)

  • Louise Rooney

    (The University of Melbourne)

  • Maria Isabel G. Lopez Sanchez

    (Royal Victorian Eye and Ear Hospital)

  • Lerna Gulluyan

    (The University of Melbourne)

  • Joao A. Paulo

    (Harvard Medical School)

  • Linda Clarke

    (Royal Victorian Eye and Ear Hospital)

  • Lisa S. Kearns

    (Royal Victorian Eye and Ear Hospital)

  • Vikkitharan Gnanasambandapillai

    (Garvan Institute of Medical Research)

  • Chia-Ling Chan

    (Garvan Institute of Medical Research)

  • Uyen Nguyen

    (Garvan Institute of Medical Research)

  • Angela M. Steinmann

    (Garvan Institute of Medical Research)

  • Rachael A. McCloy

    (Garvan Institute of Medical Research)

  • Nona Farbehi

    (Garvan Institute of Medical Research)

  • Vivek K. Gupta

    (Macquarie University)

  • David A. Mackey

    (University of Western Australia
    University of Tasmania)

  • Guy Bylsma

    (University of Western Australia)

  • Nitin Verma

    (University of Tasmania)

  • Stuart MacGregor

    (QIMR Berghofer Medical Research Institute)

  • Matthew J. Watt

    (The University of Melbourne)

  • Robyn H. Guymer

    (Royal Victorian Eye and Ear Hospital
    The University of Melbourne)

  • Joseph E. Powell

    (Garvan Institute of Medical Research
    University of New South Wales)

  • Alex W. Hewitt

    (Royal Victorian Eye and Ear Hospital
    University of Tasmania
    The University of Melbourne
    University of Tasmania)

  • Alice Pébay

    (The University of Melbourne
    Royal Victorian Eye and Ear Hospital
    The University of Melbourne)

Abstract

There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.

Suggested Citation

  • Anne Senabouth & Maciej Daniszewski & Grace E. Lidgerwood & Helena H. Liang & Damián Hernández & Mehdi Mirzaei & Stacey N. Keenan & Ran Zhang & Xikun Han & Drew Neavin & Louise Rooney & Maria Isabel G, 2022. "Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31707-4
    DOI: 10.1038/s41467-022-31707-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31707-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31707-4?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. Olivier Delaneau & Halit Ongen & Andrew A. Brown & Alexandre Fort & Nikolaos I. Panousis & Emmanouil T. Dermitzakis, 2017. "A complete tool set for molecular QTL discovery and analysis," Nature Communications, Nature, vol. 8(1), pages 1-7, August.
    2. Yibo Yu & Yu Weng & Jing Guo & Guangdi Chen & Ke Yao, 2013. "Association of Glutathione S transferases Polymorphisms with Glaucoma: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-7, January.
    3. Ryan Lister & Mattia Pelizzola & Yasuyuki S. Kida & R. David Hawkins & Joseph R. Nery & Gary Hon & Jessica Antosiewicz-Bourget & Ronan O’Malley & Rosa Castanon & Sarit Klugman & Michael Downes & Ruth , 2011. "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells," Nature, Nature, vol. 471(7336), pages 68-73, March.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Rebecca San Gil & Dana Pascovici & Juliana Venturato & Heledd Brown-Wright & Prachi Mehta & Lidia Madrid San Martin & Jemma Wu & Wei Luan & Yi Kit Chui & Adekunle T. Bademosi & Shilpa Swaminathan & Se, 2024. "A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

    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. Claire Vinel & Gabriel Rosser & Loredana Guglielmi & Myrianni Constantinou & Nicola Pomella & Xinyu Zhang & James R. Boot & Tania A. Jones & Thomas O. Millner & Anaelle A. Dumas & Vardhman Rakyan & Je, 2021. "Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    2. Elizabeth C. Goode & Laura Fachal & Nikolaos Panousis & Loukas Moutsianas & Rebecca E. McIntyre & Benjamin Yu Hang Bai & Norihito Kawasaki & Alexandra Wittmann & Tim Raine & Simon M. Rushbrook & Carl , 2024. "Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Fasil Tekola-Ayele & Xuehuo Zeng & Suvo Chatterjee & Marion Ouidir & Corina Lesseur & Ke Hao & Jia Chen & Markos Tesfaye & Carmen J. Marsit & Tsegaselassie Workalemahu & Ronald Wapner, 2022. "Placental multi-omics integration identifies candidate functional genes for birthweight," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Anyou Wang & Ying Du & Qianchuan He & Chunxiao Zhou, 2013. "A Quantitative System for Discriminating Induced Pluripotent Stem Cells, Embryonic Stem Cells and Somatic Cells," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.
    5. Zhao Wang & Qian Liang & Xinyi Qian & Bolang Hu & Zhanye Zheng & Jianhua Wang & Yuelin Hu & Zhengkai Bao & Ke Zhao & Yao Zhou & Xiangling Feng & Xianfu Yi & Jin Li & Jiandang Shi & Zhe Liu & Jihui Hao, 2023. "An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    6. Patricia Gerdes & Sue Mei Lim & Adam D. Ewing & Michael R. Larcombe & Dorothy Chan & Francisco J. Sanchez-Luque & Lucinda Walker & Alexander L. Carleton & Cini James & Anja S. Knaupp & Patricia E. Car, 2022. "Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Nikolaos M. R. Lykoskoufis & Evarist Planet & Halit Ongen & Didier Trono & Emmanouil T. Dermitzakis, 2024. "Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    8. Lakhal-Chaieb Lajmi & Greenwood Celia M.T. & Ouhourane Mohamed & Zhao Kaiqiong & Abdous Belkacem & Oualkacha Karim, 2017. "A smoothed EM-algorithm for DNA methylation profiles from sequencing-based methods in cell lines or for a single cell type," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 16(5-6), pages 313-331, December.
    9. Satria P. Sajuthi & Jamie L. Everman & Nathan D. Jackson & Benjamin Saef & Cydney L. Rios & Camille M. Moore & Angel C. Y. Mak & Celeste Eng & Ana Fairbanks-Mahnke & Sandra Salazar & Jennifer Elhawary, 2022. "Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Anneke Brümmer & Sven Bergmann, 2024. "Disentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    11. Antje Häder & Sascha Schäuble & Jan Gehlen & Nadja Thielemann & Benedikt C. Buerfent & Vitalia Schüller & Timo Hess & Thomas Wolf & Julia Schröder & Michael Weber & Kerstin Hünniger & Jürgen Löffler &, 2023. "Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. Andrew A. Brown & Juan J. Fernandez-Tajes & Mun-gwan Hong & Caroline A. Brorsson & Robert W. Koivula & David Davtian & Théo Dupuis & Ambra Sartori & Theodora-Dafni Michalettou & Ian M. Forgie & Jonath, 2023. "Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    13. Tayma Handal & Sarah Juster & Manar Abu Diab & Shira Yanovsky-Dagan & Fouad Zahdeh & Uria Aviel & Roni Sarel-Gallily & Shir Michael & Ester Bnaya & Shulamit Sebban & Yosef Buganim & Yotam Drier & Vinc, 2024. "Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Xena Marie Mapel & Naveen Kumar Kadri & Alexander S. Leonard & Qiongyu He & Audald Lloret-Villas & Meenu Bhati & Maya Hiltpold & Hubert Pausch, 2024. "Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    15. Tina Roostaei & Hans-Ulrich Klein & Yiyi Ma & Daniel Felsky & Pia Kivisäkk & Sarah M. Connor & Alexandra Kroshilina & Christina Yung & Belinda J. Kaskow & Xiaorong Shao & Brooke Rhead & José M. Ordová, 2021. "Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    16. M. A. Zouache & B. T. Richards & C. M. Pappas & R. A. Anstadt & J. Liu & T. Corsetti & S. Matthews & N. A. Seager & S. Schmitz-Valckenberg & M. Fleckenstein & W. C. Hubbard & J. Thomas & J. L. Hageman, 2024. "Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    17. Jingting Xu & Hong Hu & Yang Dai, 2016. "LMethyR-SVM: Predict Human Enhancers Using Low Methylated Regions based on Weighted Support Vector Machines," PLOS ONE, Public Library of Science, vol. 11(9), pages 1-18, September.
    18. Sun Shuying & Yu Xiaoqing, 2016. "HMM-Fisher: identifying differential methylation using a hidden Markov model and Fisher’s exact test," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(1), pages 55-67, March.
    19. Yu Xiaoqing & Sun Shuying, 2016. "HMM-DM: identifying differentially methylated regions using a hidden Markov model," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(1), pages 69-81, March.
    20. Gabriel E. Rech & Santiago Radío & Sara Guirao-Rico & Laura Aguilera & Vivien Horvath & Llewellyn Green & Hannah Lindstadt & Véronique Jamilloux & Hadi Quesneville & Josefa González, 2022. "Population-scale long-read sequencing uncovers transposable elements associated with gene expression variation and adaptive signatures in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-16, 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:13:y:2022:i:1:d:10.1038_s41467-022-31707-4. 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.