Home > Publications Database > Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies. > print

001     284046
005     20260203104145.0
024 7 _ |a 10.1038/s41380-025-03136-4
|2 doi
024 7 _ |a pmid:40830579
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024 7 _ |a pmc:PMC12815664
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024 7 _ |a 1359-4184
|2 ISSN
024 7 _ |a 1476-5578
|2 ISSN
037 _ _ |a DZNE-2026-00081
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Shen, Xueyi
|0 0000-0002-0538-4774
|b 0
245 _ _ |a Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies.
260 _ _ |a [London]
|c 2026
|b Springer Nature
336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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 (βICV = -0.017, pICV = 1.97 × 10-6; βSurf = -0.013, pSurf = 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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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Major Depressive Disorder: genetics
|2 MeSH
650 _ 2 |a Major Depressive Disorder: pathology
|2 MeSH
650 _ 2 |a Multifactorial Inheritance: genetics
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Genetic Predisposition to Disease: genetics
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Magnetic Resonance Imaging: methods
|2 MeSH
650 _ 2 |a Genome-Wide Association Study: methods
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Neuroimaging: methods
|2 MeSH
650 _ 2 |a Risk Factors
|2 MeSH
650 _ 2 |a Polymorphism, Single Nucleotide: genetics
|2 MeSH
700 1 _ |a Toenders, Yara J
|0 0000-0002-4117-1143
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700 1 _ |a Han, Laura K M
|0 0000-0001-9647-3723
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700 1 _ |a Weihs, Antoine
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700 1 _ |a Alexander, Nina
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700 1 _ |a Andlauer, Till F M
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700 1 _ |a Brosch, Katharina
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700 1 _ |a Forstner, Andreas J
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700 1 _ |a Grotegerd, Dominik
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700 1 _ |a Hahn, Tim
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700 1 _ |a Hermesdorf, Marco
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700 1 _ |a Hosten, Norbert
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700 1 _ |a Jamalabadi, Hamidreza
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700 1 _ |a Meinert, Susanne
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700 1 _ |a Milaneschi, Yuri
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700 1 _ |a Sämann, Philipp G
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700 1 _ |a Stein, Frederike
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700 1 _ |a Stolicyn, Aleks
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700 1 _ |a Teutenberg, Lea
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700 1 _ |a Thng, Gladi
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700 1 _ |a Adams, Mark J
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700 1 _ |a Thomas-Odenthal, Florian
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700 1 _ |a Usemann, Paula
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700 1 _ |a Völker, Uwe
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700 1 _ |a Wittfeld, Katharina
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700 1 _ |a Herrera-Rivero, Marisol
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700 1 _ |a Jiang, Yunxuan
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700 1 _ |a Tian, Chao
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700 1 _ |a Team, 23andMe Research
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700 1 _ |a Groenewold, Nynke A
|0 0000-0002-0865-8427
|b 29
700 1 _ |a Koopowitz, Sheri-Michelle
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700 1 _ |a Strike, Lachlan T
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700 1 _ |a Dannlowski, Udo
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700 1 _ |a Jansen, Andreas
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700 1 _ |a Kircher, Tilo
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700 1 _ |a Nenadić, Igor
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700 1 _ |a Sim, Kang
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700 1 _ |a Straube, Benjamin
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700 1 _ |a Völzke, Henry
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700 1 _ |a Stein, Dan J
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700 1 _ |a Medland, Sarah E
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700 1 _ |a Berger, Klaus
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700 1 _ |a Grabe, Hans
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700 1 _ |a Krug, Axel
|0 0000-0002-0564-2497
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700 1 _ |a McMahon, Katie L
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700 1 _ |a de Zubicaray, Greig
|0 0000-0003-4506-0579
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700 1 _ |a Pozzi, Elena
|b 46
700 1 _ |a Veltman, Dick J
|b 47
700 1 _ |a Thomopoulos, Sophia I
|b 48
700 1 _ |a Jahanshad, Neda
|b 49
700 1 _ |a Thompson, Paul M
|b 50
700 1 _ |a Schmaal, Lianne
|0 0000-0001-9822-048X
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700 1 _ |a McIntosh, Andrew M
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700 1 _ |a Whalley, Heather C
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|b 53
700 1 _ |a group, ENIGMA MDD working
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700 1 _ |a de Zubicaray, Greig
|b 55
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773 _ _ |a 10.1038/s41380-025-03136-4
|g Vol. 31, no. 2, p. 611 - 621
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|t Molecular psychiatry
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