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Integrative genetic analysis: cornerstone of precision psychiatry

Molecular Psychiatry volume 30, pages 229–236 (2025)Cite this article

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Abstract

The role of genetic testing in the domain of neurodevelopmental and psychiatric disorders (NPDs) is gradually changing from providing etiological explanation for the presence of NPD phenotypes to also identifying young individuals at high risk of developing NPDs before their clinical manifestation. In clinical practice, the latter implies a shift towards the availability of individual genetic information predicting a certain liability to develop an NPD (e.g., autism, intellectual disability, psychosis etc.). The shift from mostly a posteriori explanation to increasingly a priori risk prediction is the by-product of the systematic implementation of whole exome or genome sequencing as part of routine diagnostic work-ups during the neonatal and prenatal periods. This rapid uptake of genetic testing early in development has far-reaching consequences for psychiatry: Whereas until recently individuals would come to medical attention because of signs of abnormal developmental and/or behavioral symptoms, increasingly, individuals are presented based on genetic liability for NPD outcomes before NPD symptoms emerge. This novel clinical scenario, while challenging, also creates opportunities for research on prevention interventions and precision medicine approaches. Here, we review why optimization of individual risk prediction is a key prerequisite for precision medicine in the sphere of NPDs, as well as the technological and statistical methods required to achieve this ambition.

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Fig. 1: The change in timing of genetic diagnosis juxtaposes two different scenarios.
Fig. 2: Modelling prediction gains of integrating common and rare variant data.
Fig. 3: Sample size requirements (n per group) for four intervention trials (expected response rate 20, 30, 40 and 50% respectively).

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Acknowledgements

We thank Dr Robert W Davies at the Department of Statistics, University of Oxford, Oxford, UK, for writing the code underpinning Fig. 2b. This work was supported by the SickKids Psychiatry Associates Chair in Developmental (JV) and by NIH grants U01MH119741-01 (JV) and U01MH119746 (JS). These funding sources did not influence content of this manuscript.

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Authors and Affiliations

  1. Department of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada

    Jacob Vorstman

  2. Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Jacob Vorstman

  3. Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

    Jacob Vorstman

  4. Department of Psychiatry, Department of Cellular & Molecular Medicine, Beyster Center of Psychiatric Genomics, University of California San Diego, San Diego, CA, USA

    Jonathan Sebat

  5. Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada

    Vincent-Raphaël Bourque & Sébastien Jacquemont

  6. Department of Psychiatry, McGill University, Montréal, QC, Canada

    Vincent-Raphaël Bourque

  7. Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada

    Sébastien Jacquemont

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JV, JS, VRB and SJ contributed to the conception of the topic of this expert review as well as to the writing of the different iterations of this work. JV, JS, VRB and SJ approved the final manuscript.

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JV has served as a consultant for Nobias Therapeutics Inc. and has received speaker fees for Henry Stewart Talks Ltd.

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Vorstman, J., Sebat, J., Bourque, VR. et al. Integrative genetic analysis: cornerstone of precision psychiatry. Mol Psychiatry 30, 229–236 (2025). https://doi.org/10.1038/s41380-024-02706-2

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