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Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies

Molecular Psychiatry volume 28, pages 4943–4953 (2023)Cite this article

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Abstract

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical ‘splitting’ and ‘lumping’ approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.

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Fig. 1: Dimensional and transdiagnostic GWAS phenotypes across the lifespan.
Fig. 2: “Lumping” and “Splitting” of dimensional GWAS phenotypes.

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Data availability

No empirical data was generated in this literature review. GWAS summary statistics used in Table 1 can be downloaded from the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc/results-and-downloads/), dbGaP (accession number phs001672.v10.p1.), and Edinburgh DataShare (https://datashare.ed.ac.uk/handle/10283/3203).

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Acknowledgements

This work was supported by the National Institute of Mental Health (R21 MH123908) and the Centers for Disease Control and Prevention (U01 OH011864). GB, TCE, and EV are part funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

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Author notes

  1. These authors contributed equally: Monika A. Waszczuk, Katherine G. Jonas.

Authors and Affiliations

  1. Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    Monika A. Waszczuk

  2. Department of Psychiatry, Stony Brook University School of Medicine, Stony Brook, NY, USA

    Katherine G. Jonas & Roman Kotov

  3. Department of Psychology, University of South Florida, Tampa, FL, USA

    Marina Bornovalova

  4. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Gerome Breen, Thalia C. Eley & Evangelos Vassos

  5. UK National Institute for Health and Care Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK

    Gerome Breen, Thalia C. Eley & Evangelos Vassos

  6. Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Cynthia M. Bulik

  7. Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Cynthia M. Bulik

  8. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Cynthia M. Bulik

  9. Huntsman Mental Health Institute, Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA

    Anna R. Docherty

  10. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Anna R. Docherty & John M. Hettema

  11. Department of Psychiatry, Texas A&M Health Sciences Center, Bryan, TX, USA

    John M. Hettema

  12. Psychology Department, University of Minnesota, Minneapolis, MN, USA

    Robert F. Krueger

  13. Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

    Todd Lencz

  14. Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY, USA

    Todd Lencz

  15. Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY, USA

    Todd Lencz

  16. Department of Psychology, University of Wisconsin, Madison, WI, USA

    James J. Li

  17. Waisman Center, University of Wisconsin, Madison, WI, USA

    James J. Li

  18. Department of Psychology, Emory University, Atlanta, GA, USA

    Irwin D. Waldman

  19. Center for Computational and Quantitative Genetics, Emory University, Atlanta, GA, USA

    Irwin D. Waldman

Authors
  1. Monika A. Waszczuk
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  2. Katherine G. Jonas
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  3. Marina Bornovalova
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Contributions

MAW and KGJ conceptualized the study, conducted the literature review, and wrote the first draft of the manuscript. KGJ conducted secondary data analysis. All co-authors critically revised the manuscript drafts and approved the final version.

Corresponding author

Correspondence to Monika A. Waszczuk.

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Competing interests

CM Bulik reports: Shire (grant recipient, Scientific Advisory Board member); Lundbeckfonden (grant recipient); Pearson (author, royalty recipient); Equip Health Inc. (Stakeholder Advisory Board). Other authors declare no conflict of interest.

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Waszczuk, M.A., Jonas, K.G., Bornovalova, M. et al. Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies. Mol Psychiatry 28, 4943–4953 (2023). https://doi.org/10.1038/s41380-023-02142-8

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  • DOI: https://doi.org/10.1038/s41380-023-02142-8

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