IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30110-3.html
   My bibliography  Save this article

Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain

Author

Listed:
  • Chun Chieh Fan

    (University of California, San Diego
    University of California, San Diego
    University of California, San Diego)

  • Robert Loughnan

    (University of California, San Diego)

  • Carolina Makowski

    (University of California, San Diego
    University of California, San Diego)

  • Diliana Pecheva

    (University of California, San Diego
    University of California, San Diego)

  • Chi-Hua Chen

    (University of California, San Diego)

  • Donald J. Hagler

    (University of California, San Diego
    University of California, San Diego)

  • Wesley K. Thompson

    (University of California, San Diego
    University of California, San Diego)

  • Nadine Parker

    (University of Oslo)

  • Dennis van der Meer

    (University of Oslo
    Maastricht University)

  • Oleksandr Frei

    (University of Oslo
    University of Oslo)

  • Ole A. Andreassen

    (University of Oslo)

  • Anders M. Dale

    (University of California, San Diego
    University of California, San Diego
    University of California, San Diego
    University of California, San Diego)

Abstract

The molecular determinants of tissue composition of the human brain remain largely unknown. Recent genome-wide association studies (GWAS) on this topic have had limited success due to methodological constraints. Here, we apply advanced whole-brain analyses on multi-shell diffusion imaging data and multivariate GWAS to two large scale imaging genetic datasets (UK Biobank and the Adolescent Brain Cognitive Development study) to identify and validate genetic association signals. We discover 503 unique genetic loci that have impact on multiple regions of human brain. Among them, more than 79% are validated in either of two large-scale independent imaging datasets. Key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development are found to significantly impact the measured variations in tissue-specific imaging features. Our results shed new light on the biological determinants of brain tissue composition and their potential overlap with the genetic basis of neuropsychiatric disorders.

Suggested Citation

  • Chun Chieh Fan & Robert Loughnan & Carolina Makowski & Diliana Pecheva & Chi-Hua Chen & Donald J. Hagler & Wesley K. Thompson & Nadine Parker & Dennis van der Meer & Oleksandr Frei & Ole A. Andreassen, 2022. "Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30110-3
    DOI: 10.1038/s41467-022-30110-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30110-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-30110-3?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. Bradley Efron, 2020. "Prediction, Estimation, and Attribution," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 115(530), pages 636-655, April.
    2. Edith Hofer & Gennady V. Roshchupkin & Hieab H. H. Adams & Maria J. Knol & Honghuang Lin & Shuo Li & Habil Zare & Shahzad Ahmad & Nicola J. Armstrong & Claudia L. Satizabal & Manon Bernard & Joshua C., 2020. "Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Dennis Meer & Oleksandr Frei & Tobias Kaufmann & Alexey A. Shadrin & Anna Devor & Olav B. Smeland & Wesley K. Thompson & Chun Chieh Fan & Dominic Holland & Lars T. Westlye & Ole A. Andreassen & Anders, 2020. "Understanding the genetic determinants of the brain with MOSTest," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    4. Bradley Efron, 2020. "Prediction, Estimation, and Attribution," International Statistical Review, International Statistical Institute, vol. 88(S1), pages 28-59, December.
    5. 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.
    6. Lloyd T. Elliott & Kevin Sharp & Fidel Alfaro-Almagro & Sinan Shi & Karla L. Miller & Gwenaëlle Douaud & Jonathan Marchini & Stephen M. Smith, 2018. "Genome-wide association studies of brain imaging phenotypes in UK Biobank," Nature, Nature, vol. 562(7726), pages 210-216, October.
    7. Kyoko Watanabe & Erdogan Taskesen & Arjen Bochoven & Danielle Posthuma, 2017. "Functional mapping and annotation of genetic associations with FUMA," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    8. Zhonghua Liu & Xihong Lin, 2019. "A Geometric Perspective on the Power of Principal Component Association Tests in Multiple Phenotype Studies," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 114(527), pages 975-990, July.
    9. Hamdan Hamdan & Brian C. Lim & Tomohiro Torii & Abhijeet Joshi & Matthias Konning & Cameron Smith & Donna J. Palmer & Philip Ng & Christophe Leterrier & Juan A. Oses-Prieto & Alma L. Burlingame & Matt, 2020. "Mapping axon initial segment structure and function by multiplexed proximity biotinylation," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    10. Elodie Persyn & Ken B. Hanscombe & Joanna M. M. Howson & Cathryn M. Lewis & Matthew Traylor & Hugh S. Markus, 2020. "Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    11. Tian Ge & Martin Reuter & Anderson M. Winkler & Avram J. Holmes & Phil H. Lee & Lee S. Tirrell & Joshua L. Roffman & Randy L. Buckner & Jordan W. Smoller & Mert R. Sabuncu, 2016. "Multidimensional heritability analysis of neuroanatomical shape," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
    12. Dennis Meer & Oleksandr Frei & Tobias Kaufmann & Alexey A. Shadrin & Anna Devor & Olav B. Smeland & Wesley K. Thompson & Chun Chieh Fan & Dominic Holland & Lars T. Westlye & Ole A. Andreassen & Anders, 2020. "Author Correction: Understanding the genetic determinants of the brain with MOSTest," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    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. E. P. Tissink & A. A. Shadrin & D. Meer & N. Parker & G. Hindley & D. Roelfs & O. Frei & C. C. Fan & M. Nagel & T. Nærland & M. Budisteanu & S. Djurovic & L. T. Westlye & M. P. Heuvel & D. Posthuma & , 2024. "Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study," Nature Communications, Nature, vol. 15(1), pages 1-13, 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. Eva-Maria Stauffer & Richard A. I. Bethlehem & Lena Dorfschmidt & Hyejung Won & Varun Warrier & Edward T. Bullmore, 2023. "The genetic relationships between brain structure and schizophrenia," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Peter Zhukovsky & Earvin S. Tio & Gillian Coughlan & David A. Bennett & Yanling Wang & Timothy J. Hohman & Diego A. Pizzagalli & Benoit H. Mulsant & Aristotle N. Voineskos & Daniel Felsky, 2024. "Genetic influences on brain and cognitive health and their interactions with cardiovascular conditions and depression," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. 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.
    4. Shahram Bahrami & Kaja Nordengen & Alexey A. Shadrin & Oleksandr Frei & Dennis Meer & Anders M. Dale & Lars T. Westlye & Ole A. Andreassen & Tobias Kaufmann, 2022. "Distributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. Mengge Liu & Lu Wang & Yujie Zhang & Haoyang Dong & Caihong Wang & Yayuan Chen & Qian Qian & Nannan Zhang & Shaoying Wang & Guoshu Zhao & Zhihui Zhang & Minghuan Lei & Sijia Wang & Qiyu Zhao & Feng Li, 2024. "Investigating the shared genetic architecture between depression and subcortical volumes," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Rebecca Shafee & Dustin Moraczewski & Siyuan Liu & Travis Mallard & Adam Thomas & Armin Raznahan, 2024. "A sex-stratified analysis of the genetic architecture of human brain anatomy," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    7. E. P. Tissink & A. A. Shadrin & D. Meer & N. Parker & G. Hindley & D. Roelfs & O. Frei & C. C. Fan & M. Nagel & T. Nærland & M. Budisteanu & S. Djurovic & L. T. Westlye & M. P. Heuvel & D. Posthuma & , 2024. "Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    8. 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.
    9. Runye Shi & Shitong Xiang & Tianye Jia & Trevor W. Robbins & Jujiao Kang & Tobias Banaschewski & Gareth J. Barker & Arun L. W. Bokde & Sylvane Desrivières & Herta Flor & Antoine Grigis & Hugh Garavan , 2024. "Investigating grey matter volumetric trajectories through the lifespan at the individual level," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    10. Michael Wainberg & Natalie J. Forde & Salim Mansour & Isabel Kerrebijn & Sarah E. Medland & Colin Hawco & Shreejoy J. Tripathy, 2024. "Genetic architecture of the structural connectome," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    11. Manski, Charles F., 2023. "Probabilistic prediction for binary treatment choice: With focus on personalized medicine," Journal of Econometrics, Elsevier, vol. 234(2), pages 647-663.
    12. Junjiao Feng & Liang Zhang & Chunhui Chen & Jintao Sheng & Zhifang Ye & Kanyin Feng & Jing Liu & Ying Cai & Bi Zhu & Zhaoxia Yu & Chuansheng Chen & Qi Dong & Gui Xue, 2022. "A cognitive neurogenetic approach to uncovering the structure of executive functions," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    13. Weishampel, Anthony & Staicu, Ana-Maria & Rand, William, 2023. "Classification of social media users with generalized functional data analysis," Computational Statistics & Data Analysis, Elsevier, vol. 179(C).
    14. Paolo Libenzio Brignoli & Alessandro Varacca & Cornelis Gardebroek & Paolo Sckokai, 2024. "Machine learning to predict grains futures prices," Agricultural Economics, International Association of Agricultural Economists, vol. 55(3), pages 479-497, May.
    15. Guanghao Qi & Surya B. Chhetri & Debashree Ray & Diptavo Dutta & Alexis Battle & Samsiddhi Bhattacharjee & Nilanjan Chatterjee, 2024. "Genome-wide large-scale multi-trait analysis characterizes global patterns of pleiotropy and unique trait-specific variants," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Xiaofeng Zhu & Yihe Yang & Noah Lorincz-Comi & Gen Li & Amy R. Bentley & Paul S. de Vries & Michael Brown & Alanna C. Morrison & Charles N. Rotimi & W. James Gauderman & Dabeeru C. Rao & Hugues Aschar, 2024. "An approach to identify gene-environment interactions and reveal new biological insight in complex traits," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    17. 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.
    18. Zhiqiang Sha & Dick Schijven & Amaia Carrion-Castillo & Marc Joliot & Bernard Mazoyer & Simon E. Fisher & Fabrice Crivello & Clyde Francks, 2021. "The genetic architecture of structural left–right asymmetry of the human brain," Nature Human Behaviour, Nature, vol. 5(9), pages 1226-1239, September.
    19. Catherine M. Francis & Matthias E. Futschik & Jian Huang & Wenjia Bai & Muralidharan Sargurupremraj & Alexander Teumer & Monique M. B. Breteler & Enrico Petretto & Amanda S. R. Ho & Philippe Amouyel &, 2022. "Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Palwende Romuald Boua & Jean-Tristan Brandenburg & Ananyo Choudhury & Hermann Sorgho & Engelbert A. Nonterah & Godfred Agongo & Gershim Asiki & Lisa Micklesfield & Solomon Choma & Francesc Xavier Góme, 2022. "Genetic associations with carotid intima-media thickness link to atherosclerosis with sex-specific effects in sub-Saharan Africans," Nature Communications, Nature, vol. 13(1), pages 1-11, 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_s41467-022-30110-3. 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.