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The impact of collider bias on genetic prediction in psychotic disorders

Neuropsychopharmacology volume 51, pages 430–439 (2026)Cite this article

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Abstract

Polygenic risk scores (PRS) have potential utility as biomarkers of psychiatric disorders. However, the potential utility of some PRS has been much clearer than others. The schizophrenia PRS has been consistently associated with diagnosis, symptom severity, and other correlates of schizophrenia. Yet despite the close genetic correlation (rg = 0.69) between bipolar disorder and schizophrenia, the bipolar (BP) PRS has been inconstantly associated with clinical course and outcomes. We hypothesize that common sample selection strategies induce collider bias between the SZ and BP PRS, in turn moderating the association between the BP PRS and clinical outcomes. Collider bias is illustrated in three effects. First, it is shown that clinical characteristics used in sample ascertainment (i.e. case status, treatment history) are a function of the SZ and BP PRSs. Second, selecting on these clinical characteristics biases the correlation between the BP and SZ PRSs. Third, selection on these clinical characteristics in turn moderates the association between the BP PRS and clinical outcomes. Effects were tested in three samples: UK Biobank (N = 337,420), a population-based sample; PsyCourse (N = 1,594), a case-control cohort of individuals with mood and psychotic disorders; and the Suffolk County Mental Health Cohort (N = 378), a first-admission psychosis cohort. In all three samples, SZ and BP PRSs were significantly correlated with case status or treatment history. In addition, correlations between SZ and BP PRS were biased in samples selected by case status or treatment history. Finally, conditioning analyses on case status moderated, and in some cases reversed, associations between the BP PRS and clinical outcomes. It is important to understand the impact of this and other forms of selection bias in evaluating PRS as biomarkers of psychiatric disorders, particularly when the intended application is populations enriched for high genetic risk.

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Fig. 1: Impact of collider bias on PRS correlations and PRS-trait associations.

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Data availability

Data from UK Biobank are available to qualified researchers. The application process is outlined at https://community.ukbiobank.ac.uk/hc/en-gb/categories/14494598931229-Enable-your-research. Data from PsyCourse are available to qualified researchers. The application process is outlined at http://www.psycourse.de/index-en.html. Data from the Suffolk County Mental Health Project are available from the NIMH Data Archive, collection number 2477. Analytic syntax is available from the corresponding author upon request.

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Acknowledgements

The authors gratefully acknowledge the support of the participants and mental health community of Suffolk County for contributing their time and energy to this project. They are also indebted to the study coordinators for their dedicated efforts, the interviewers for their careful assessments, and the psychiatrists who derived the consensus diagnoses. The authors also thank Dr. Greg Perlman for his contributions to analytic troubleshooting.

Funding

This research was supported by National Institutes of Health (MH44801, MH094398, MH110434), and a NARSAD Young Investigator Grant to R.K. This study received funding from the National Institutes of Health under grant number R21MH123908, awarded to K. J. This research has been conducted using data from UK Biobank, a major biomedical database, under project ID 55741. This work uses data provided by patients and collected by the NHS as part of their care and support. U.H. was supported by European Union’s Horizon 2020 Research and Innovation Program (PSY-PGx, grant agreement No 945151) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project number 514201724). Thomas G. Schulze was supported by the Deutsche Forschungsgemeinschaft (KFO241/PsyCourse, SCHU 1603/4-1, 5-1, 7-1), the German Ministry of Education and Research (IntegraMent: 01ZX1614K; BipoLife: 01EE1404H; the German Center for Mental Health [DZPG]: 01EE2303A/01EE2303F), and the European Union (ERA-NET NEURON - MulioBio: 01EW2009; GEPI-BIOPSY: 01EW2005).

Author information

Authors and Affiliations

  1. Department of Psychology, Stony Brook University, Stony Brook, NY, USA

    Amna Asim

  2. Department of Department of Family Population & Preventive Medicine, Stony Brook Medicine, Stony Brook, NY, USA

    Yuan Yang & Sean A. P. Clouston

  3. Institute of Psychiatric Phenomics and Genomic (IPPG), LMU University Hospital, LMU Munich, Munich, Germany

    Kristina Adorjan, Monika Budde, Maria Heilbronner, Alba Navarro-Flores, Mojtaba Oraki Kohshour, Sergi Papiol, Daniela Reich-Erkelenz, Eva C. Schulte, Thomas G. Schulze, Fanny Senner, Urs Heilbronner & Thomas Schulze

  4. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA

    Thomas Schulze

  5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Thomas Schulze

  6. Institute of Behavioral Sciences, Feinstein Institutes for Medical Research, Manhasset, NY, USA

    Todd Lencz

  7. Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA

    Todd Lencz

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

    Todd Lencz

  9. Social Genetic & Developmental Psychiatry Centre, King’s College London, London, UK

    Evangelos Vassos

  10. Department of Psychiatry & Behavioral Health, Stony Brook Medicine, Stony Brook, NY, USA

    Roman Kotov & Katherine Jonas

  11. Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, 80336, Germany

    Peter Falkai & Andrea Schmitt

  12. Department of Psychiatry and Psychotherapy, Mental Health Institute Berlin, Berlin, 14050, Germany

    Ion-George Anghelescu

  13. Institute for Translational Psychiatry, University of Münster, Münster, 48149, Germany

    Volker Arolt & Udo Dannlowski

  14. Department of Psychiatry, University of Münster, Münster, 48149, Germany

    Bernhardt T. Baune

  15. AMEOS Clinical Center Hildesheim, Hildesheim, 31135, Germany

    Detlef E. Dietrich

  16. Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health (TüCMH), University of Tübingen, Tübingen, 72076, Germany

    Andreas J. Fallgatter

  17. Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg, 26160, Germany

    Christian Figge

  18. Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, 89312, Germany

    Markus Jäger & Fabian U. Lang

  19. Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, 44791, Germany

    Georg Juckel

  20. Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum, Rotenburg, 27356, Germany

    Carsten Konrad

  21. Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Jens Reimer

  22. Division of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, 8036, Austria

    Eva Z. Reininghaus

  23. Clinic for Psychiatry, Psychotherapy and Psychosomatics, Augsburg University, Medical Faculty, Bezirkskrankenhaus Augsburg, Augsburg, 86156, Germany

    Max Schmauß

  24. Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Rostock, Rostock, 18147, Germany

    Carsten Spitzer

  25. Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, 37075, Germany

    Jens Wiltfang

  26. Psychiatrieverbund Oldenburger Land gGmbH, Karl-Jaspers-Klinik, Bad Zwischenahn, 26160, Germany

    Jörg Zimmermann

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  1. Amna Asim
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  2. Yuan Yang
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  4. Thomas Schulze
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  8. Roman Kotov
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  9. Katherine Jonas
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Consortia

PsyCourse Study

  • Kristina Adorjan
  • , Monika Budde
  • , Peter Falkai
  • , Maria Heilbronner
  • , Urs Heilbronner
  • , Alba Navarro-Flores
  • , Mojtaba Oraki Kohshour
  • , Sergi Papiol
  • , Daniela Reich-Erkelenz
  • , Eva C. Schulte
  • , Thomas G. Schulze
  • , Fanny Senner
  • , Ion-George Anghelescu
  • , Volker Arolt
  • , Bernhardt T. Baune
  • , Udo Dannlowski
  • , Detlef E. Dietrich
  • , Andreas J. Fallgatter
  • , Christian Figge
  • , Markus Jäger
  • , Fabian U. Lang
  • , Georg Juckel
  • , Carsten Konrad
  • , Jens Reimer
  • , Eva Z. Reininghaus
  • , Max Schmauß
  • , Andrea Schmitt
  • , Carsten Spitzer
  • , Jens Wiltfang
  •  & Jörg Zimmermann

Contributions

Amna Asim wrote the initial draft. Yuan Yang performed data analyses. The PsyCourse Study curated data. Urs Heilbronner and Thomas Schulze contributed to data curation, provided computing resources, and reviewed and edited the manuscript. Todd Lencz, Evangelos Vassos, and Sean Clouston reviewed and edited the manuscript. Roman Kotov contributed to conceptualization, project funding, data curation, and reviewed and edited the manuscript. Katherine Jonas conceptualized the study, obtained funding, administered the project, supervised, and revised the manuscript.

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Correspondence to Katherine Jonas.

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Asim, A., Yang, Y., PsyCourse Study. et al. The impact of collider bias on genetic prediction in psychotic disorders. Neuropsychopharmacol. 51, 430–439 (2026). https://doi.org/10.1038/s41386-025-02285-y

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