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Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders

Nature Mental Health volume 2, pages 189–199 (2024)Cite this article

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Abstract

Psychiatric disorders are complex, heritable and highly polygenic. Supported by findings of abnormalities in functional magnetic resonance imaging-based measures of brain connectivity, current theoretical and empirical accounts have conceptualized them as disorders of brain connectivity and dysfunctional integration of brain signaling. However, the extent to which these findings reflect common genetic factors remains unclear. Here we performed a multivariate genome-wide association analysis of functional magnetic resonance imaging-based functional brain connectivity in a sample of 30,701 individuals from the UK Biobank and investigated the shared genetic determinants with eight major psychiatric disorders. The analysis revealed significant genetic overlap between functional brain connectivity and schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety and major depression, adding further genetic support for the dysconnectivity hypothesis of psychiatric disorders and identifying potential genetic and functional targets for future studies.

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Fig. 1: Multivariate and univariate architecture of the brain functional connectome highlight a distributed nature of effects across the brain.
Fig. 2: Heritability across edges and nodes.
Fig. 3: Manhattan plots illustrating genetic overlap between disorders and the multivariate functional brain phenotypes.
Fig. 4: Genetic correlation between the connectome and psychiatric disorders.

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Data availability

Data used in this study are part of the publicly available UK Biobank initiative (https://www.ukbiobank.ac.uk/). Summary statistics for the disorders are publicly available through their respective consortia (Supplementary Table 1). The summary statistics for the multivariate analyses are available on GitHub (https://www.github.com/norment/open-science).

Code availability

Code is publicly available on GitHub (https://www.github.com/norment/open-science).

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Acknowledgements

The authors were funded by the Research Council of Norway (#276082 LifespanHealth, #323961 BRAINGAP, #223273 NORMENT, #283798 ERA-NET Neuron SYNSCHIZ, #249795, #298646 and #300767), the South-East Norway Regional Health Authority (2019101, 2019107 and 2020086) and the European Research Council under the European Union’s Horizon2020 Research and Innovation program (ERC Starting Grant #802998), as well as the Horizon2020 Research and Innovation Action Grant CoMorMent (#847776). This research has been conducted using the UK Biobank Resource (access code 27412, https://www.ukbiobank.ac.uk/). This work was performed on the TSD (Tjenester for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT). Computations were also performed on resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway.

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Authors and Affiliations

  1. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Daniel Roelfs, Dennis van der Meer, Dag Alnæs, Oleksandr Frei, Alexey A. Shadrin, Ole A. Andreassen, Lars T. Westlye & Tobias Kaufmann

  2. School of Mental Health and Neuroscience, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, the Netherlands

    Dennis van der Meer

  3. Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway

    Oleksandr Frei

  4. Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA

    Robert Loughnan

  5. Population Neuroscience and Genetics Lab, University of California, San Diego, CA, USA

    Chun Chieh Fan

  6. Center for Human Development, University of California, San Diego, CA, USA

    Chun Chieh Fan

  7. Department of Radiology, School of Medicine, University of California, San Diego, CA, USA

    Chun Chieh Fan

  8. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA

    Anders M. Dale

  9. Center for Multimodal Imaging and Genetics, University of California at San Diego, La Jolla, CA, USA

    Anders M. Dale

  10. K.G. Jebsen Center for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway

    Anders M. Dale, Ole A. Andreassen & Lars T. Westlye

  11. Department of Psychology, University of Oslo, Oslo, Norway

    Lars T. Westlye

  12. Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, Tübingen, Germany

    Tobias Kaufmann

  13. German Center for Mental Health (DZPG), partner site Tübingen, Tübingen, Germany

    Tobias Kaufmann

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Contributions

D.R. and T.K. conceived the study; D.R. analyzed the data with contributions from T.K.; D.R., D.v.d.M., D.A., O.F., A.A.S., R.L., C.C.F., A.M.D., O.A.A., L.T.W. and T.K. contributed with conceptual input on methods and/or interpretation of results; D.R. and T.K. wrote the first draft of the paper, and D.R., D.v.d.M., D.A., O.F., A.A.S., R.L., C.C.F., A.M.D., O.A.A., L.T.W. and T.K. contributed to the final manuscript.

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Correspondence to Daniel Roelfs or Tobias Kaufmann.

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Competing interests

D.R., D.v.d.M., D.A., O.F., A.A.S., R.L., C.C.F., L.T.W. and T.K. declare no conflicts of interest. O.A.A. is a consultant to HealthLytix and received speakers honorarium from Lundbeck. A.M.D. is a Founder of and holds equity in CorTechs Labs, Inc., and serves on its Scientific Advisory Board. The terms of this arrangement have been reviewed and approved by UCSD in accordance with its conflict of interest policies.

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Nature Mental Health thanks Andrew Grotzinger and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Roelfs, D., van der Meer, D., Alnæs, D. et al. Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders. Nat. Mental Health 2, 189–199 (2024). https://doi.org/10.1038/s44220-023-00190-1

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