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Dissecting causal relationships between cortical morphology and neuropsychiatric disorders: a bidirectional Mendelian randomization study

Nature Mental Health volume 3, pages 613–625 (2025)Cite this article

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Abstract

Brain cortical morphology, indexed by its surface area and thickness, is known to be highly heritable. Previous research has suggested a relationship of cortical morphology with several neuropsychiatric phenotypes. However, the multitude of potential confounders makes it difficult to establish causal relationships. Here we employ generalized summary-data-based Mendelian randomization and a series of sensitivity analyses to investigate causal links between 70 cortical morphology measures and 199 neuropsychiatric, behavioral and metabolic phenotypes. We show that total brain cortical surface area (TSA) has significant positive causal effects on 18 phenotypes. The strongest effects include TSA positively influencing cognitive performance, while reverse analyses reveal small effects of cognitive performance on TSA. Global mean cortical thickness (MTH) exhibits significant causal effects on five phenotypes, including schizophrenia. MTH reduces schizophrenia risk, and bidirectional causality is found between MTH and smoking initiation. Finally, in regional analyses, we detect positive influences of the transverse temporal surface area on cognitive performance and negative influences of transverse temporal thickness on schizophrenia risk. Overall, our results highlight bidirectional associations between TSA, MTH and neuropsychiatric traits. These insights offer potential avenues for intervention studies aimed at improving brain health.

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Fig. 1: Overview of our study design.
Fig. 2: GSMR models with significant results (Pfdr < 0.05) for ΤSA and ΜTH.
Fig. 3: Bidirectional MR analyses using several models to examine causal relationships between TSA and CP and between MTH and SCZ3.
Fig. 4: Regional plots for SA with CP.
Fig. 5: Regional plots for TH with SCZ3.

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Data availability

All results of data generated and analyzed during this study are included in Supplementary Information and Supplementary Data Tables 1–11. These files provide the complete dataset necessary to interpret, verify and extend the research presented in the Article. For any additional information or access to specific datasets beyond those provided, reasonable requests can be made to the corresponding author.

Code availability

The code used for data analysis is available via GitHub (https://github.com/Bochao1/Brian_NMH).

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Acknowledgements

We acknowledge the authors of the original GWAS studies who shared (either publicly or privately) the GWAS summary statistics, encouraging data accessibility and thus scientific collaboration. D.v.d.M. is funded by the Research Council of Norway (no. 324252). Y.L. is funded by the Natural Science Foundation of Gansu Province, China (no. 22JR5RA728). K.L.G. is funded by the National Health and Medical Research Council (APP1173025). S.G., B.P.F.R. and B.D.L. are supported by the YOUTH-GEMs project, funded by the European Union’s Horizon Europe program under grant agreement number 101057182. No funding was provided to carry out this work.

Author information

Author notes

  1. These authors contributed equally: Bochao Danae Lin, Yunzhi Li, Anastasia A. Goula.

  2. These authors jointly supervised this work: Dennis van der Meer, Jurjen J. Luykx.

Authors and Affiliations

  1. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands

    Bochao Danae Lin, Yunzhi Li, Bart P. F. Rutten, Sinan Guloksuz, Dennis van der Meer & Jurjen J. Luykx

  2. Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, School of Basic Medical Sciences, Henan University, Kaifeng, China

    Bochao Danae Lin

  3. Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

    Bochao Danae Lin & Anastasia A. Goula

  4. Department of Radiology, Gansu Provincial Maternity and Child-care Hospital (Gansu Province Central Hospital), Lanzhou, China

    Yunzhi Li

  5. Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China

    Xiao Chang

  6. Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Katrina L. Grasby & Sarah Medland

  7. Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Ole A. Andreassen & Dennis van der Meer

  8. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Sinan Guloksuz

  9. Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands

    Jurjen J. Luykx

  10. GGZ inGeest Mental Health Care, Amsterdam, the Netherlands

    Jurjen J. Luykx

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Contributions

B.D.L., Y.L. and A.A.G. wrote the first draft. J.J.L. conceived the study and conducted project management. B.D.L. conceptualized the data analysis plan, performed the data analysis and drafted the methods and results sections. Y.L. and A.A.G. contributed to data interpretation and paper drafting. Y.L. wrote sections of the discussion, while A.A.G. wrote sections of the introduction. X.C., K.L.G., S.M., O.A.A., B.P.F.R. and S.G. provided critical feedback on the methodology and statistical analysis. D.v.d.M. and J.J.L., who share senior authorship, oversaw the entire project, contributed to the study design and finalized the paper. All authors reviewed and approved the final paper.

Corresponding author

Correspondence to Jurjen J. Luykx.

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Nature Mental Health thanks Shinichiro Luke Nakajima and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–7, Tables 1–4, Methods and Results.

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Supplementary Data Tables 1–11 and a README sheet to explain the contents.

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Lin, B.D., Li, Y., Goula, A.A. et al. Dissecting causal relationships between cortical morphology and neuropsychiatric disorders: a bidirectional Mendelian randomization study. Nat. Mental Health 3, 613–625 (2025). https://doi.org/10.1038/s44220-025-00397-4

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