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Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia

Molecular Psychiatry volume 28, pages 2071–2080 (2023)Cite this article

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Abstract

22q11.2 deletion is one of the strongest known genetic risk factors for schizophrenia. Recent whole-genome sequencing of schizophrenia cases and controls with this deletion provided an unprecedented opportunity to identify risk modifying genetic variants and investigate their contribution to the pathogenesis of schizophrenia in 22q11.2 deletion syndrome. Here, we apply a novel analytic framework that integrates gene network and phenotype data to investigate the aggregate effects of rare coding variants and identified modifier genes in this etiologically homogenous cohort (223 schizophrenia cases and 233 controls of European descent). Our analyses revealed significant additive genetic components of rare nonsynonymous variants in 110 modifier genes (adjusted P = 9.4E-04) that overall accounted for 4.6% of the variance in schizophrenia status in this cohort, of which 4.0% was independent of the common polygenic risk for schizophrenia. The modifier genes affected by rare coding variants were enriched with genes involved in synaptic function and developmental disorders. Spatiotemporal transcriptomic analyses identified an enrichment of coexpression between modifier and 22q11.2 genes in cortical brain regions from late infancy to young adulthood. Corresponding gene coexpression modules are enriched with brain-specific protein-protein interactions of SLC25A1, COMT, and PI4KA in the 22q11.2 deletion region. Overall, our study highlights the contribution of rare coding variants to the SCZ risk. They not only complement common variants in disease genetics but also pinpoint brain regions and developmental stages critical to the etiology of syndromic schizophrenia.

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Fig. 1: Statistical framework to examine the aggregate effects of modifier rare coding variants on SCZ.
Fig. 2: SCZ risk from rare coding variants in 22q11.2DS.
Fig. 3: Composition of genetic risk of SCZ in the study cohort.
Fig. 4: Gene-set enrichment analysis of modifier genes.
Fig. 5: Transcriptomic analyses of modifier and 22q11.2 genes in brain development.

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Data availability

This study is a secondary data analysis of the whole genome sequencing data of SCZ in 22q11.2DS generated by the International 22q11.2DS Brain and Behavior Consortium (IBBC). All summary statistics for the SCZ association of rare coding variants in the IBBC 22q11.2DS cohort are available at http://zdzlab.einsteinmed.edu/1/sz-22q.html. All predicted modifier genes are available in the supplementary material. Due to privacy concerns for our research participants, individual-level genetic data from the IBBC study of SCZ in 22q11.2DS are not publicly available; however, access to anonymized data can be requested from a qualified academic investigator to the IBBC Executive Committee, providing the data transfer is approved by the Institutional Review Board and regulated by a material transfer agreement.

Code availability

IGSP is publicly available at https://zenodo.org/record/1034362#.X-JWQNgzY2w. All other software used in our analyses is open source and described in “Methods”.

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Acknowledgements

This work was supported by funding to ZDZ from NIH Grants U01 MH101720, R01 AG057909, U19 AG056278, R01 AG061521, R01 AG057706, RF1 AG057341, R01 AG061155, P01 AG047200, P01 AG017242, P30 AG038072, and a Career Scientist Award from the Irma T. Hirschl Trust.

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  1. A list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA

    Jhih-Rong Lin, Yingjie Zhao, M. Reza Jabalameli, Nha Nguyen, Joydeep Mitra, Bernice E. Morrow, Herbert M. Lachman & Zhengdong D. Zhang

  2. Department of Human Genetics, KU Leuven, Leuven, Belgium

    Ann Swillen & Joris R. Vermeesch

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Jacob A. S. Vorstman, Eva W. C. Chow & Anne S. Bassett

  4. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK

    Marianne van den Bree, Michael J. Owen & Nigel M. Williams

  5. Division of Human Genetics and 22q and You Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Beverly S. Emanuel & Donna M. McDonald-McGinn

  6. Department of Psychiatry and Lifespan Brain Institute, Penn Medicine—CHOP, University of Pennsylvania, Philadelphia, PA, USA

    Raquel E. Gur

  7. Departments of Psychiatry and Biobehavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA

    Carrie E. Bearden

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  1. Jhih-Rong Lin
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International 22q11.DS Brain and Behavior Consortium

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Correspondence to Zhengdong D. Zhang.

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Lin, JR., Zhao, Y., Jabalameli, M.R. et al. Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia. Mol Psychiatry 28, 2071–2080 (2023). https://doi.org/10.1038/s41380-023-02009-y

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