Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies

Xueyi Shen¹, Yara J Toenders², Laura K M Han^{3

4

5}, Antoine Weihs^{6

7}, Nina Alexander⁸, Till F M Andlauer⁹, Katharina Brosch⁸, Andreas J Forstner^{10

11

12}, Dominik Grotegerd¹³, Tim Hahn¹³, Marco Hermesdorf¹⁴, Norbert Hosten¹⁵, Hamidreza Jamalabadi⁸, Susanne Meinert^{13

16}, Yuri Milaneschi^{5

17

18}, Philipp G Sämann¹⁹, Frederike Stein⁸, Aleks Stolicyn²⁰, Lea Teutenberg⁸, Gladi Thng²⁰, Mark J Adams²⁰, Florian Thomas-Odenthal⁸, Paula Usemann⁸, Uwe Völker²¹, Katharina Wittfeld⁶, Marisol Herrera-Rivero¹⁴, Yunxuan Jiang²², Chao Tian²²; 23andMe Research Team; Nynke A Groenewold²³, Sheri-Michelle Koopowitz²³, Lachlan T Strike²⁴, Udo Dannlowski¹³, Andreas Jansen⁸, Tilo Kircher⁸, Igor Nenadić⁸, Kang Sim^{25

26

27}, Benjamin Straube⁸, Henry Völzke²⁸, Dan J Stein^{23

29}, Sarah E Medland²⁴, Klaus Berger¹⁴, Hans J Grabe⁶, Axel Krug³⁰, Katie L McMahon³¹, Greig de Zubicaray³², Elena Pozzi^{3

4}, Dick J Veltman³³, Sophia I Thomopoulos³⁴, Neda Jahanshad³⁴, Paul M Thompson³⁴, Lianne Schmaal^{3

4}, Andrew M McIntosh²⁰, Heather C Whalley²⁰; ENIGMA MDD working group

Collaborators, Affiliations

Collaborators

ENIGMA MDD working group:
Greig de Zubicaray

Affiliations

¹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK. Xueyi.shen@ed.ac.uk.
² Erasmus School of Social and Behavioral Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands.
³ Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁴ Orygen, Parkville, VIC, Australia.
⁵ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁷ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Germany.
⁸ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
⁹ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
¹⁰ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹¹ Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
¹² Centre for Human Genetics, Philipps-University Marburg, Marburg, Germany.
¹³ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹⁴ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁵ Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹⁶ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
¹⁷ Amsterdam Public Health, Mental Health program, Amsterdam, The Netherlands.
¹⁸ Amsterdam Neuroscience, Complex Trait Genetics, Amsterdam, The Netherlands.
¹⁹ Max Planck Institute of Psychiatry, Munich, Germany.
²⁰ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
²¹ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
²² 23andMe, San Francisco, CA, USA.
²³ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
²⁴ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁵ West Region, Institute of Mental Health, Singapore, Singapore.
²⁶ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
²⁷ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
²⁸ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²⁹ SAMRC Research Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
³⁰ Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.
³¹ School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
³² School of Psychology and Counselling, Queensland University of Technology, Brisbane, QLD, Australia.
³³ Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, The Netherlands.
³⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

PMID: 40830579
DOI: 10.1038/s41380-025-03136-4

Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies

Xueyi Shen et al. Mol Psychiatry. 2025.

. 2025 Aug 19.

doi: 10.1038/s41380-025-03136-4. Online ahead of print.

Authors

Collaborators

ENIGMA MDD working group:
Greig de Zubicaray

Affiliations

¹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK. Xueyi.shen@ed.ac.uk.
² Erasmus School of Social and Behavioral Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands.
³ Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁴ Orygen, Parkville, VIC, Australia.
⁵ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁷ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Germany.
⁸ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
⁹ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
¹⁰ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹¹ Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
¹² Centre for Human Genetics, Philipps-University Marburg, Marburg, Germany.
¹³ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹⁴ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁵ Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹⁶ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
¹⁷ Amsterdam Public Health, Mental Health program, Amsterdam, The Netherlands.
¹⁸ Amsterdam Neuroscience, Complex Trait Genetics, Amsterdam, The Netherlands.
¹⁹ Max Planck Institute of Psychiatry, Munich, Germany.
²⁰ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
²¹ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
²² 23andMe, San Francisco, CA, USA.
²³ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
²⁴ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁵ West Region, Institute of Mental Health, Singapore, Singapore.
²⁶ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
²⁷ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
²⁸ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²⁹ SAMRC Research Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
³⁰ Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.
³¹ School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
³² School of Psychology and Counselling, Queensland University of Technology, Brisbane, QLD, Australia.
³³ Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, The Netherlands.
³⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

PMID: 40830579
DOI: 10.1038/s41380-025-03136-4

Abstract

Major Depression (MD) is a prevalent, disabling and life-limiting condition. The neurobiological associations of genetic risk for MD remain under-explored in large samples, with no comprehensive mega-analysis conducted to date. Our study analysed data from 11 separate studies, encompassing 50,975 participants from the ENIGMA Major Depressive Disorder Working Group. We developed highly consistent genetic and neuroimaging protocols and applied these throughout all participating studies, together with rigorous genetic methods to remove overlap between the polygenic risk scores (PRS) training and testing samples. Elevated PRS for MD correlated with lower intracranial volume and lower global measure of cortical surface area (β_ICV = -0.017, p_ICV = 1.97 × 10^-6; β_Surf = -0.013, p_Surf = 4.5 × 10^-4; pFDR < 3.62 × 10^-4). The most significant cortical association was observed in the surface area of the frontal lobe (β = -0.011, p = 2.85 × 10^-6, pFDR = 1.42 × 10^-5), particularly in the left medial orbito-frontal gyrus (β = -0.021, p = 9.48 × 10^-8, pFDR = 1.25 × 10^-5). In subcortical regions, lower volumes of the thalamus, hippocampus, and pallidum correlated with higher PRS of MD (β ranged from -0.011 to -0.015, p ranged from 0.002-1.73 × 10^-5, pFDR < 0.006). In a subsample of young individuals only (<25 years old, N = 5570), although there were no FDR-significant findings, directions of effects were highly consistent between the analyses of cortical surface areas in youth and the full sample (71.2% in the same direction, exact binomial test p-value = 7.56 × 10^-4). Subsequent Mendelian randomisation analysis revealed potentially causal effects of smaller left hippocampal volume on higher liability for MD (Inverse variance weighted analysis β = -0.064, p = 8.04 × 10^-3, pFDR = 0.04). Our findings represent an example of how extensive international collaborations can significantly advance our neurogenetic understanding of MD and give insights to avenues for early interventions in those at high risk for developing MD.

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Conflict of interest statement

Competing interests: Yunxuan Jiang, Chao Tian are employed by and hold stock or stock options in 23andMe, Inc. Dr. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. Hans J. Grabe has received travel grants and speakers’ honoraria from Neuraxpharm, Servier, Indorsia and Janssen Cilag. PMT received partial research support from Biogen, Inc., for research unrelated to this manuscript. No other authors have conflict of interest to declare. Ethics approval and consent to participate: The study was approved by the NHS Tayside Research Ethics committee (05/s1401/89). Written consents were obtained from all participants from each individual ENIGMA cohort and publicly available datasets. All analyses and interpretation were performed under the guidance of the World Medical Association’s Declaration of Helsinki ( https://www.wma.net/policies-post/wma-declaration-of-helsinki/ ). The use, sharing and anonymisation for genetic and neuroimaging data were conducted under the EU General Data Protection Regulation ( https://gdpr-info.eu/ ). Analyses and data management followed the guidelines of the UK Medical Research Council’s ‘Research, GDPR & Confidentiality’ training. Access to UK Biobank individual-level was obtained under the application #4844. The ABCD study was approved by the National Institute of Mental Health Data Archive, United States (NIMH), and data was accessed through the NDA data base (Federal-Wide Assurance: FWA00018101).

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Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies

Collaborators

Affiliations

Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous