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Mendelian randomization analyses support causal relationships between brain imaging-derived phenotypes and risk of psychiatric disorders

Nature Neuroscience volume 25, pages 1519–1527 (2022)Cite this article

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Abstract

Observational studies have reported the correlations between brain imaging-derived phenotypes (IDPs) and psychiatric disorders; however, whether the relationships are causal is uncertain. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the causalities between 587 reliable IDPs (N = 33,224 individuals) and 10 psychiatric disorders (N = 9,725 to 161,405). We identified nine IDPs for which there was evidence of a causal influence on risk of schizophrenia, anorexia nervosa and bipolar disorder. For example, 1 s.d. increase in the orientation dispersion index of the forceps major was associated with 32% lower odds of schizophrenia risk. Reverse MR indicated that only genetically predicted schizophrenia was positively associated with two IDPs, the cortical surface area and the volume of the right pars orbitalis. We established the BrainMR database (http://www.bigc.online/BrainMR/) to share our results. Our findings provide potential strategies for the prediction and intervention for psychiatric disorder risk at the brain-imaging level.

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Fig. 1: Workflow of the causal inference between IDPs 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 data are publicly available with the exception of the posttraumatic stress disorder data from Gelernter et al.67. These data are available through dbGaP accession number phs001672.v1.p1. Major depressive disorder GWAS data without the UK Biobank data were obtained by contacting the Psychiatric Genomics Consortium workgroup data access committee representative (https://www.med.unc.edu/pgc/pgc-workgroups/major-depressive-disorder/). The GWASs for other psychiatric disorders were provided by the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc). Download links for all public datasets are available in Supplementary Table 2. The GWASs for brain IDPs can be obtained from the BIG40 web browser (https://open.win.ox.ac.uk/ukbiobank/big40/). Data in the NHGRI-EBI GWAS Catalog (v1.0.2-associtions_e104, released on 22 October 2021) were downloaded from https://www.ebi.ac.uk/gwas/docs/file-downloads/. Our results in the study are presented in our online platform at http://www.bigc.online/BrainMR/.

Code availability

The actual code used to run the analyses described in this study is available at our online platform (http://www.bigc.online/BrainMR/Browse/1.2-Code.html). All software packages we used in the study are publicly available, and the download links are included in the Methods.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant numbers 32170616 (T.-L.Y.), 82170896 (Y.G.), 31970569 (Y.G.) and 82101601 (S.Y.)), Science Fund for Distinguished Young Scholars of Shaanxi Province (grant number 2021JC-02 (T.-L.Y.)), Innovation Capability Support Program of Shaanxi Province (grant number 2022TD-44 (T.-L.Y.)) and the Fundamental Research Funds for the Central Universities (T.-L.Y.). This work was also supported by the High-Performance Computing Platform and Instrument Analysis Center of Xi’an Jiaotong University. We would like to thank the UK Biobank and Cross-Disorder Group of the Psychiatric Genomics Consortium for the GWAS summary data of IDPs and psychiatric disorders. We also thank the US Million Veteran Program and dbGaP. The GWAS summary data of posttraumatic stress disorder that we used are available from the dbGaP database under dbGaP accession number phs001672.v1.p1. We thank the UK Biobank Resource under application number 46387.

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Author notes

  1. These authors contributed equally: Jing Guo, Ke Yu, Shan-Shan Dong.

Authors and Affiliations

  1. Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, P. R. China

    Jing Guo, Ke Yu, Shan-Shan Dong, Yu Rong, Hao Wu, Kun Zhang, Feng Jiang, Yan Guo & Tie-Lin Yang

  2. National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, P. R. China

    Shi Yao & Yi-Xiao Chen

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  1. Jing Guo
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Contributions

J.G. conducted this project and wrote the manuscript. K.Y. built the database website and drew the figures. S.-S.D. and Y.G. revised the manuscript. S.Y. applied for the UK Biobank data and offered some advice. Y.R. and H.W. drew the figures and collected materials for the online database. K.Z. and F.J. summarized the UK Biobank data. Y.-X.C. applied for the dbGaP data. T.-L.Y. and Y.G. conceived and supervised this project.

Corresponding authors

Correspondence to Yan Guo or Tie-Lin Yang.

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Nature Neuroscience thanks Baptiste Couvy-Duchesne, Miguel Renteria, and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–4 and note for the GWAS datasets.

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Supplementary Table

Supplementary Tables 1–15.

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Guo, J., Yu, K., Dong, SS. et al. Mendelian randomization analyses support causal relationships between brain imaging-derived phenotypes and risk of psychiatric disorders. Nat Neurosci 25, 1519–1527 (2022). https://doi.org/10.1038/s41593-022-01174-7

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