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Functional connectome-wide associations of schizophrenia polygenic risk

Molecular Psychiatry volume 26, pages 2553–2561 (2021)Cite this article

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Abstract

Schizophrenia is a highly heritable mental disorder characterized by functional dysconnectivity across the brain. However, the relationships between polygenic risk factors and connectome-wide neural mechanisms are unclear. Here, combining genetic and multiparadigm fMRI data of 623 healthy Caucasian adults drawn from the Human Connectome Project, we found that higher schizophrenia polygenic risk scores were significantly correlated with lower functional connectivity in a large-scale brain network primarily encompassing the visual system, default-mode system, and frontoparietal system. Such correlation was robustly observed across multiple fMRI paradigms, suggesting a brain-state-independent neural phenotype underlying individual genetic liability to schizophrenia. Moreover, using an independent clinical dataset acquired from the Consortium for Neuropsychiatric Phenomics, we further demonstrated that the connectivity of the identified network was reduced in patients with schizophrenia and significantly correlated with general cognitive ability. These findings provide the first evidence for connectome-wide associations of schizophrenia polygenic risk at the systems level and suggest that disrupted integration of sensori–cognitive information may be a hallmark of genetic effects on the brain that contributes to the pathogenesis of schizophrenia.

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Fig. 1: Flowchart of the data processing pipeline used in the study.
Fig. 2: Connectome-wide associations of PRS in the HCP data.
Fig. 3: Clinical and cognitive relevance of the PRS-related network in the CNP data.

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Code availability

All toolboxes used in this study are freely available. PLINK 1.9 is available at https://www.cog-genomics.org/plink2, PRSice-2 is available at https://choishingwan.github.io/PRSice/, and the NBS toolbox is available at https://www.nitrc.org/projects/nbs/.

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Acknowledgements

This work was supported by the Brain and Behavior Research Foundation NARSAD Young Investigator Grant (No. 27068) to HC, by National Institute of Health (NIH) grants U01 MH081902 to TDC, and by gifts from the Staglin Music Festival for Mental Health and International Mental Health Research Organization to TDC. Authors would like to thank Kevin Anderson (Yale Psychology) for suggestions on genetic data analysis.

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  1. Department of Psychology, Yale University, New Haven, CT, USA

    Hengyi Cao & Tyrone D. Cannon

  2. Department of Psychiatry, Yale University, New Haven, CT, USA

    Hang Zhou & Tyrone D. Cannon

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Correspondence to Hengyi Cao.

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TDC has served as a consultant for Boehringer-Ingelheim Pharmaceuticals and Lundbeck A/S. The other authors report no conflicts of interest.

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Cao, H., Zhou, H. & Cannon, T.D. Functional connectome-wide associations of schizophrenia polygenic risk. Mol Psychiatry 26, 2553–2561 (2021). https://doi.org/10.1038/s41380-020-0699-3

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