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Adult ADHD with comorbid major depression shows a distinguishable polygenic pattern and negative cognitive style
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  • Published: 04 April 2026

Adult ADHD with comorbid major depression shows a distinguishable polygenic pattern and negative cognitive style

  • Thorsten M. Kranz  ORCID: orcid.org/0000-0002-7233-93081,
  • Rhiannon V. McNeill  ORCID: orcid.org/0000-0002-3297-92122,
  • Christian P. Jacob3,
  • Kira F. Ahrens  ORCID: orcid.org/0000-0002-3249-04091,
  • Rebecca J. Neumann  ORCID: orcid.org/0000-0001-9523-94251,
  • Michael M. Plichta  ORCID: orcid.org/0000-0002-7161-06881,
  • Bianca Kollmann  ORCID: orcid.org/0000-0002-4894-27564,5,
  • Fabian Streit  ORCID: orcid.org/0000-0003-1080-43396,7,8,
  • Oliver Tüscher  ORCID: orcid.org/0000-0002-4023-53014,5,9,
  • Klaus Lieb  ORCID: orcid.org/0000-0002-9609-42614,
  • Heike Weber  ORCID: orcid.org/0000-0002-9421-12922,
  • Marcel Romanos  ORCID: orcid.org/0000-0001-7628-829910,
  • Klaus-Peter Lesch  ORCID: orcid.org/0000-0001-8348-153X10,11,12,
  • Andreas Reif  ORCID: orcid.org/0000-0002-0992-634X1,13,
  • Sarah Kittel-Schneider  ORCID: orcid.org/0000-0003-3057-61502,14 &
  • …
  • Georg C. Ziegler  ORCID: orcid.org/0000-0001-9411-31692,11 

Translational Psychiatry , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • ADHD
  • Clinical genetics
  • Depression
  • Predictive markers

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, and comorbidity with other mental diseases is common. Specifically, adult ADHD (aADHD) is highly comorbid with major depressive disorder (MDD). A genetic correlation between ADHD and MDD might underlie the risk of comorbidity of both disorders. However, whether patients with ADHD and comorbid MDD differ genetically from those without comorbid MDD is currently unclear. We therefore studied the genetic background of an aADHD cohort including 352 patients with lifetime MDD and 349 patients with no history of depression, assessed by SCID-I. Polygenic risk scores for ADHD (PRS-ADHD) and MDD (PRS-MDD) were derived from large-scale genome-wide association studies. These PRS were first regressed using aADHD patients (n = 894) vs. healthy controls (n = 1026), and then using comorbidity and dimensional traits in the aADHD cohort. Both PRS-ADHD and PRS-MDD were associated with ADHD (PRS-ADHD: OR = 1.59, p < 0.0001; PRS-MDD: OR = 1.41, p < 0.0001), but only PRS-MDD was associated with comorbid MDD in aADHD patients (OR = 1.34, p < 0.001). Notably, patients with a history of combined MDD and anxiety disorders had the highest PRS-MDD. ADHD patients with a history of MDD had higher odds for other internalizing disorders, showed significantly more inattentive symptoms, higher neuroticism scores, lower childhood social confidence, and were more often treated as psychiatric inpatients. These findings suggest that comorbidity between aADHD and MDD is associated with genetic susceptibility to MDD, rather than neurodevelopmental factors intrinsic to ADHD pathophysiology. Our results also strengthen the view that comorbid MDD in aADHD is linked to an inattentive-internalizing rather than an impulsive-externalizing psychopathological factor.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank all funding agencies that supported our research. We are grateful to all patients for their participation in the study and their constant enthusiasm despite the challenges of living with ADHD.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft (CRC 1193 subproject Z03; DFG CRU 125), the DYNAMIC center, which is funded by the LOEWE program of the Hessian Ministry of Science and Arts (Grant Number: LOEWE1/16/519/03/09.001(0009)/98), and the EU Horizon 2020 Research and Innovation Programme under Grant No. 667302 (CoCA) and No. 728018 (Eat2beNICE), and by the ECNP Network ‘ADHD across the Lifespan’ (https://www.ecnp.eu/researchinnovation/ECNP-networks/List-ECNP-Networks/). FS was supported by the Hector foundation II. This publication was supported by the Open Access Publication Fund of the University of Würzburg. None of the funding sources had a role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Open Access funding enabled and organized by Projekt DEAL.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany

    Thorsten M. Kranz, Kira F. Ahrens, Rebecca J. Neumann, Michael M. Plichta & Andreas Reif

  2. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany

    Rhiannon V. McNeill, Heike Weber, Sarah Kittel-Schneider & Georg C. Ziegler

  3. Department of Psychiatry and Psychotherapy, Medius Hospital of Kirchheim, Kirchheim unter Teck, Germany

    Christian P. Jacob

  4. Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center, Mainz, Germany

    Bianca Kollmann, Oliver Tüscher & Klaus Lieb

  5. Leibniz Institute for Resilience Research, Mainz, Germany

    Bianca Kollmann & Oliver Tüscher

  6. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Fabian Streit

  7. Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Fabian Streit

  8. German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany

    Fabian Streit

  9. Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Martin Luther University Halle-Wittenberg (MLU) & German Center for Mental Health (DZPG), partner site Halle-Jena-Magdeburg, Halle, Germany

    Oliver Tüscher

  10. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany

    Marcel Romanos & Klaus-Peter Lesch

  11. Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany

    Klaus-Peter Lesch & Georg C. Ziegler

  12. Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

    Klaus-Peter Lesch

  13. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany

    Andreas Reif

  14. Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland

    Sarah Kittel-Schneider

Authors
  1. Thorsten M. Kranz
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  2. Rhiannon V. McNeill
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  3. Christian P. Jacob
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  4. Kira F. Ahrens
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  5. Rebecca J. Neumann
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  6. Michael M. Plichta
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  10. Klaus Lieb
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  15. Sarah Kittel-Schneider
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  16. Georg C. Ziegler
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Contributions

GCZ and TMK wrote the first draft of the manuscript and carried out the statistical analyses. GCZ, TMK, and AR designed the study. KL, KPL, AR, and SKS had a supervisory role. RVM, CPJ, KFA, RJN, MMP, BK, FS, OT, HW and MR were involved in data collection and analysis. All authors contributed to manuscript writing and approved the final version of the manuscript.

Corresponding author

Correspondence to Georg C. Ziegler.

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CPJ received speakers’ fees from derCampus, Daiichi Sankyo, Janssen-Cilag, Eli Lilly and Co, Shire, Novartis, and Medice. AR has received honoraria for lectures and/or advisory boards from Janssen, Boehringer Ingelheim, COMPASS, SAGE/Biogen, LivaNova, Medice, Shire/Takeda, MSD and cyclerion. Also, he has received research grants from Medice and Janssen. SKS has received speaker’s honoraria from Takeda, Medice and Janssen. None of the other authors reports any financial conflict of interest related to this work.

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Kranz, T.M., McNeill, R.V., Jacob, C.P. et al. Adult ADHD with comorbid major depression shows a distinguishable polygenic pattern and negative cognitive style. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-04008-3

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  • Received: 17 January 2025

  • Revised: 12 March 2026

  • Accepted: 24 March 2026

  • Published: 04 April 2026

  • DOI: https://doi.org/10.1038/s41398-026-04008-3

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