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Mendelian randomization analyses reveal causal relationships between brain functional networks and risk of psychiatric disorders

Nature Human Behaviour (2024)Cite this article

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Abstract

Dysfunction of brain resting-state functional networks has been widely reported in psychiatric disorders. However, the causal relationships between brain resting-state functional networks and psychiatric disorders remain largely unclear. Here we perform bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causalities between 191 resting-state functional magnetic resonance imaging (rsfMRI) phenotypes (n = 34,691 individuals) and 12 psychiatric disorders (n = 14,307 to 698,672 individuals). Forward MR identified 8 rsfMRI phenotypes causally associated with the risk of psychiatric disorders. For example, the increase in the connectivity of motor, subcortical-cerebellum and limbic network was associated with lower risk of autism spectrum disorder. In adddition, increased connectivity in the default mode and central executive network was associated with lower risk of post-traumatic stress disorder and depression. Reverse MR analysis revealed significant associations between 4 psychiatric disorders and 6 rsfMRI phenotypes. For instance, the risk of attention-deficit/hyperactivity disorder increases the connectivity of the attention, salience, motor and subcortical-cerebellum network. The risk of schizophrenia mainly increases the connectivity of the default mode and central executive network and decreases the connectivity of the attention network. In summary, our findings reveal causal relationships between brain functional networks and psychiatric disorders, providing important interventional and therapeutic targets for psychiatric disorders at the brain functional network level.

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Fig. 1: Workflow of bidirectional MR analysis between brain rsfMRI and psychiatric disorders.
Fig. 2: Causalities in the forward MR.
Fig. 3: Causalities in the reverse MR.

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Data availability

All GWAS summary statistical data in this study are publicly available. The GWAS dataset for birth length was downloaded from the Early Growth Genetics Consortium (http://egg-consortium.org), and the GWAS summary statistics for height was downloaded from the GIANT 2014 cohort (http://www.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium). The GWAS summary statistics for anxiety disorder, post-traumatic stress disorder and alcohol use disorder from MVP were obtained via dbGAP (dbGaP accession: phs001672.v9.p1). The GWAS summary statistics for insomnia was obtained from FinnGen R9 release (https://storage.googleapis.com/finngen-public-data-r9/summary_stats/finngen_R9_F5_INSOMNIA.gz), the GWAS summary statistics for Alzheimer’s disease was obtained from Center for Neurogenomics and Cognitive Research (https://ctg.cncr.nl/software/summary_statistics/), and GWAS datasets for other psychiatric disorders were obtained from PGC (https://pgc.unc.edu/for-researchers/download-results). The datasets for the brain rsfMRI can be obtained via Zenodo at https://zenodo.org/record/5775047 (ref. 119). Source data are provided with this paper.

Code availability

The custom codes used in the study are available on GitHub at https://github.com/Dangxl/fMRI-MR-analysis. All software packages used are publicly available.

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Acknowledgements

This study was equally supported by the National Nature Science Foundation of China (U2102205), start-up funds from Southeast University (RF1028623032), and the Key Project of Yunnan Fundamental Research Projects (202101AS070055), and was also supported by the Distinguished Young Scientists grant of Yunnan Province (202001AV070006). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank Z. Ding and Q. Li for technical assistance.

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  1. These authors contributed equally: Changgai Mu, Xinglun Dang.

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  1. Department of Psychosomatics and Psychiatry, Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China

    Changgai Mu, Xinglun Dang & Xiong-Jian Luo

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  1. Changgai Mu
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Contributions

X.-J.L. conceived, designed and supervised the whole study. C.M. and X.D. conducted the analyses and drafted the manuscript. X.-J.L. oversaw the project, revised and finalized the manuscript. All authors revised the manuscript critically and approved the final version.

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Correspondence to Xiong-Jian Luo.

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Mu, C., Dang, X. & Luo, XJ. Mendelian randomization analyses reveal causal relationships between brain functional networks and risk of psychiatric disorders. Nat Hum Behav (2024). https://doi.org/10.1038/s41562-024-01879-8

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