IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49263-4.html
   My bibliography  Save this article

Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression

Author

Listed:
  • Ruo-Han Hao

    (Xi’an Jiaotong University)

  • Tian-Pei Zhang

    (Xi’an Jiaotong University)

  • Feng Jiang

    (Xi’an Jiaotong University)

  • Jun-Hui Liu

    (Xi’an Jiaotong University)

  • Shan-Shan Dong

    (Xi’an Jiaotong University)

  • Meng Li

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Yan Guo

    (Xi’an Jiaotong University)

  • Tie-Lin Yang

    (Xi’an Jiaotong University
    The First Affiliated Hospital of Xi’an Jiaotong University)

Abstract

The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.

Suggested Citation

  • Ruo-Han Hao & Tian-Pei Zhang & Feng Jiang & Jun-Hui Liu & Shan-Shan Dong & Meng Li & Yan Guo & Tie-Lin Yang, 2024. "Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49263-4
    DOI: 10.1038/s41467-024-49263-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49263-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-49263-4?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. Atsushi Takata & Naomichi Matsumoto & Tadafumi Kato, 2017. "Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci," Nature Communications, Nature, vol. 8(1), pages 1-11, April.
    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. Anya Topiwala & Kulveer Mankia & Steven Bell & Alastair Webb & Klaus P. Ebmeier & Isobel Howard & Chaoyue Wang & Fidel Alfaro-Almagro & Karla Miller & Stephen Burgess & Stephen Smith & Thomas E. Nicho, 2023. "Association of gout with brain reserve and vulnerability to neurodegenerative disease," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    4. Gao Wang & Abhishek Sarkar & Peter Carbonetto & Matthew Stephens, 2020. "A simple new approach to variable selection in regression, with application to genetic fine mapping," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 82(5), pages 1273-1300, December.
    5. 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.
    6. Dmitry Shungin & Thomas W. Winkler & Damien C. Croteau-Chonka & Teresa Ferreira & Adam E. Locke & Reedik Mägi & Rona J. Strawbridge & Tune H. Pers & Krista Fischer & Anne E. Justice & Tsegaselassie Wo, 2015. "New genetic loci link adipose and insulin biology to body fat distribution," Nature, Nature, vol. 518(7538), pages 187-196, February.
    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. Cecilia Pessoa Rodrigues & Aindrila Chatterjee & Meike Wiese & Thomas Stehle & Witold Szymanski & Maria Shvedunova & Asifa Akhtar, 2021. "Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    2. Parsa Akbari & Olukayode A. Sosina & Jonas Bovijn & Karl Landheer & Jonas B. Nielsen & Minhee Kim & Senem Aykul & Tanima De & Mary E. Haas & George Hindy & Nan Lin & Ian R. Dinsmore & Jonathan Z. Luo , 2022. "Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Saaket Agrawal & Minxian Wang & Marcus D. R. Klarqvist & Kirk Smith & Joseph Shin & Hesam Dashti & Nathaniel Diamant & Seung Hoan Choi & Sean J. Jurgens & Patrick T. Ellinor & Anthony Philippakis & Me, 2022. "Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Hazewinkel, Audinga-Dea & Richmond, Rebecca C. & Wade, Kaitlin H. & Dixon, Padraig, 2022. "Mendelian randomization analysis of the causal impact of body mass index and waist-hip ratio on rates of hospital admission," Economics & Human Biology, Elsevier, vol. 44(C).
    5. Yang, Chiao-Yu & Lei, Lihua & Ho, Nhat & Fithian, William, 2022. "BONuS: Multiple Multivariate Testing with a Data-Adaptive Test Statistic," Research Papers 4031, Stanford University, Graduate School of Business.
    6. Jaakko Pehkonen & Jutta Viinikainen & Jaana T. Kari & Petri Böckerman & Terho Lehtimäki & Olli Raitakari, 2021. "Birth weight and adult income: An examination of mediation through adult height and body mass," Health Economics, John Wiley & Sons, Ltd., vol. 30(10), pages 2383-2398, September.
    7. 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.
    8. 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.
    9. Yi Huang & Anyongqi Wang & Wenjiang Zhou & Baoguo Li & Linshan Zhang & Agata M. Rudolf & Zengguang Jin & Catherine Hambly & Guanlin Wang & John R. Speakman, 2024. "Maternal dietary fat during lactation shapes single nucleus transcriptomic profile of postnatal offspring hypothalamus in a sexually dimorphic manner in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Isabelle Austin-Zimmerman & Daniel F. Levey & Olga Giannakopoulou & Joseph D. Deak & Marco Galimberti & Keyrun Adhikari & Hang Zhou & Spiros Denaxas & Haritz Irizar & Karoline Kuchenbaecker & Andrew M, 2023. "Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. Jie Huang & Jennifer E. Huffman & Yunfeng Huang & Ítalo Valle & Themistocles L. Assimes & Sridharan Raghavan & Benjamin F. Voight & Chang Liu & Albert-László Barabási & Rose D. L. Huang & Qin Hui & Xu, 2022. "Genomics and phenomics of body mass index reveals a complex disease network," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    12. Samuel Baker & Pietro Biroli & Hans van Kippersluis & Stephanie von Hinke, 2022. "Beyond Barker: Infant Mortality at Birth and Ischaemic Heart Disease in Older Age," Bristol Economics Discussion Papers 22/765, School of Economics, University of Bristol, UK.
    13. Viinikainen, Jutta & Bryson, Alex & Böckerman, Petri & Kari, Jaana T. & Lehtimäki, Terho & Raitakari, Olli & Viikari, Jorma & Pehkonen, Jaakko, 2022. "Does better education mitigate risky health behavior? A mendelian randomization study," Economics & Human Biology, Elsevier, vol. 46(C).
    14. Nathan LaPierre & Kodi Taraszka & Helen Huang & Rosemary He & Farhad Hormozdiari & Eleazar Eskin, 2021. "Identifying causal variants by fine mapping across multiple studies," PLOS Genetics, Public Library of Science, vol. 17(9), pages 1-19, September.
    15. Sarah Meulebrouck & Judith Merrheim & Gurvan Queniat & Cyril Bourouh & Mehdi Derhourhi & Mathilde Boissel & Xiaoyan Yi & Alaa Badreddine & Raphaël Boutry & Audrey Leloire & Bénédicte Toussaint & Souhi, 2024. "Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    16. Sophie A. Riesmeijer & Zoha Kamali & Michael Ng & Dmitriy Drichel & Bram Piersma & Kerstin Becker & Thomas B. Layton & Jagdeep Nanchahal & Michael Nothnagel & Ahmad Vaez & Hans Christian Hennies & Pau, 2024. "A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    17. Mateus H. Gouveia & Amy R. Bentley & Thiago P. Leal & Eduardo Tarazona-Santos & Carlos D. Bustamante & Adebowale A. Adeyemo & Charles N. Rotimi & Daniel Shriner, 2023. "Unappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    18. Sonali Pechlivanis & Susanne Moebus & Nils Lehmann & Raimund Erbel & Amir A Mahabadi & Per Hoffmann & Karl-Heinz Jöckel & Markus M Nöthen & Hagen S Bachmann & on behalf of the Heinz Nixdorf Recall Stu, 2020. "Genetic risk scores for coronary artery disease and its traditional risk factors: Their role in the progression of coronary artery calcification—Results of the Heinz Nixdorf Recall study," PLOS ONE, Public Library of Science, vol. 15(5), pages 1-18, May.
    19. Yunfeng Huang & Dora Bodnar & Chia-Yen Chen & Gabriela Sanchez-Andrade & Mark Sanderson & Jun Shi & Katherine G. Meilleur & Matthew E. Hurles & Sebastian S. Gerety & Ellen A. Tsai & Heiko Runz, 2023. "Rare genetic variants impact muscle strength," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    20. Anat Kreimer & Tal Ashuach & Fumitaka Inoue & Alex Khodaverdian & Chengyu Deng & Nir Yosef & Nadav Ahituv, 2022. "Massively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, 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_s41467-024-49263-4. 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.