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Changes in polygenic burden for psychiatric disorders across two decades of birth cohorts

Nature Mental Health volume 3, pages 1037–1045 (2025) Cite this article

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Abstract

During recent decades, the incidence of several psychiatric disorders has increased, but no previous study has investigated whether the polygenic burden based on common variants for psychiatric disorders in diagnosed individuals has changed over time. Here we aimed to explore changes in polygenic scores for schizophrenia, depression, autism and attention deficit hyperactivity disorder (ADHD) in the general population and in case populations according to birth cohorts. The iPSYCH2015 is a Danish population-based case–cohort study, including individuals born between 1981 and 2008, who were followed for a psychiatric diagnosis between 1994 and 2015. We included 41,132 individuals from the random subcohort and 60,293 individuals diagnosed with schizophrenia spectrum disorders, depression, autism or ADHD. We estimated changes in polygenic scores across birth years based on linear regression. The average polygenic score was stable in the random subcohort but decreased across birth years in case populations, most predominantly for schizophrenia (per 10 years: −0.13 s.d., 95% confidence interval (CI) −0.18 to −0.07) but also for depression (−0.06 s.d., 95% CI −0.10 to −0.03) and autism (−0.08 s.d., 95% CI −0.13 to −0.04) and to a limited degree for ADHD (−0.03 s.d., 95% CI −0.08 to 0.02). Moreover, we estimated how the hazard ratio for being diagnosed given a 1 s.d. increase in polygenic score changed according to birth year, which decreased for schizophrenia but remained stable for the other disorders. Finally, we estimated the number of additional cases per 1 s.d. increase in polygenic score according to birth year, which decreased for both schizophrenia and depression, whereas autism and ADHD showed increases. In conclusion, the polygenic burden for psychiatric disorders changed across two decades among diagnosed individuals in Denmark. For schizophrenia, the polygenic score itself and its predictive ability decreased over time, whereas depression, autism and ADHD showed diverse changes.

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Fig. 1: Changes over time in PGS distributions across birth cohorts.
The alternative text for this image may have been generated using AI.
Fig. 2: Hazard ratio and number of additional cases given a 1 s.d. increase in PGS in three birth cohort periods.
The alternative text for this image may have been generated using AI.

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Data availability

Data presented in this study were obtained from Danish registries and biobanks. Owing to data protection rules, we are not allowed to share individual-level data. Other researchers can apply for such data, if relevant.

Code availability

The programming code for statistical analyses is available via the Open Science Framework at https://osf.io/8hx4k.

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Acknowledgements

We gratefully acknowledge the Psychiatric Genomics Consortium and the research participants and employees of 23andMe, Inc. for providing the summary statistics used to generate the PGSs. This project was supported by Independent Research Fund Denmark (Sapere Aude Fellowship no. 2066-00009B to O.P.-R.). O.P.-R. has also received funding from Independent Research Fund Denmark (grant no. 1030-00085B) and the Lundbeck Foundation (grant no. R345-2020-1588). A.J.S. received funding from the Lundbeck Foundation (grant no. R335-2019-2318). B.J.V received funding from the Lundbeck Foundation (grant no. R335-2019-2339) and the Independent Research Fund Denmark (grant no. 2034-00241B). S.L. received funding from the Research Fund of the Mental Health Services–Capital Region of Denmark (grant no. R4A92).

Author information

Author notes

  1. These authors contributed equally: Andrew J. Schork, Oleguer Plana-Ripoll.

Authors and Affiliations

  1. Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark

    Mette Lise Lousdal & Oleguer Plana-Ripoll

  2. National Centre for Register-based Research, Department of Public Health, Aarhus University, Aarhus, Denmark

    Mette Lise Lousdal, Esben Agerbo, Clara Albiñana, Bjarni J. Vilhjálmsson, John J. McGrath & Oleguer Plana-Ripoll

  3. Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark

    Sonja LaBianca & Andrew J. Schork

  4. Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

    Esben Agerbo

  5. Big Data Institute, University of Oxford, Oxford, UK

    Clara Albiñana

  6. Department of Psychiatry, University of Oxford, Oxford, UK

    Clara Albiñana

  7. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    Bjarni J. Vilhjálmsson

  8. Novo Nordisk Foundation Center for Genomics Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Bjarni J. Vilhjálmsson

  9. Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia

    John J. McGrath

  10. Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia

    John J. McGrath

  11. Lundbeck Foundation Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark

    Andrew J. Schork

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Contributions

M.L.L., S.L., E.A., A.J.S. and O.P.-R. designed the study. C.A. and B.J.V. derived the PGSs. With help from S.L., A.J.S. and O.P.-R., M.L.L. conducted the data analysis. M.L.L. and O.P.-R. wrote the first draft of the paper, which was subsequently revised for important intellectual content by the remaining authors. M.L.L., S.L., E.A., C.A., B.J.V., J.J.M., A.J.S. and O.P.-R. contributed to the interpretation of the results and approved the final paper prior to submission.

Corresponding authors

Correspondence to Mette Lise Lousdal or Oleguer Plana-Ripoll.

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Nature Mental Health thanks Laísa Camerini, Davide Piffer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Lousdal, M.L., LaBianca, S., Agerbo, E. et al. Changes in polygenic burden for psychiatric disorders across two decades of birth cohorts. Nat. Mental Health 3, 1037–1045 (2025). https://doi.org/10.1038/s44220-025-00478-4

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