TY  - JOUR
AU  - Shen, Xueyi
AU  - Toenders, Yara J
AU  - Han, Laura K M
AU  - Weihs, Antoine
AU  - Alexander, Nina
AU  - Andlauer, Till F M
AU  - Brosch, Katharina
AU  - Forstner, Andreas J
AU  - Grotegerd, Dominik
AU  - Hahn, Tim
AU  - Hermesdorf, Marco
AU  - Hosten, Norbert
AU  - Jamalabadi, Hamidreza
AU  - Meinert, Susanne
AU  - Milaneschi, Yuri
AU  - Sämann, Philipp G
AU  - Stein, Frederike
AU  - Stolicyn, Aleks
AU  - Teutenberg, Lea
AU  - Thng, Gladi
AU  - Adams, Mark J
AU  - Thomas-Odenthal, Florian
AU  - Usemann, Paula
AU  - Völker, Uwe
AU  - Wittfeld, Katharina
AU  - Herrera-Rivero, Marisol
AU  - Jiang, Yunxuan
AU  - Tian, Chao
AU  - Groenewold, Nynke A
AU  - Koopowitz, Sheri-Michelle
AU  - Strike, Lachlan T
AU  - Dannlowski, Udo
AU  - Jansen, Andreas
AU  - Kircher, Tilo
AU  - Nenadić, Igor
AU  - Sim, Kang
AU  - Straube, Benjamin
AU  - Völzke, Henry
AU  - Stein, Dan J
AU  - Medland, Sarah E
AU  - Berger, Klaus
AU  - Grabe, Hans
AU  - Krug, Axel
AU  - McMahon, Katie L
AU  - de Zubicaray, Greig
AU  - Pozzi, Elena
AU  - Veltman, Dick J
AU  - Thomopoulos, Sophia I
AU  - Jahanshad, Neda
AU  - Thompson, Paul M
AU  - Schmaal, Lianne
AU  - McIntosh, Andrew M
AU  - Whalley, Heather C
TI  - Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies.
JO  - Molecular psychiatry
VL  - 31
IS  - 2
SN  - 1359-4184
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2026-00081
SP  - 611 - 621
PY  - 2026
AB  - 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
KW  - Humans
KW  - Major Depressive Disorder: genetics
KW  - Major Depressive Disorder: pathology
KW  - Multifactorial Inheritance: genetics
KW  - Male
KW  - Female
KW  - Genetic Predisposition to Disease: genetics
KW  - Brain: pathology
KW  - Adult
KW  - Magnetic Resonance Imaging: methods
KW  - Genome-Wide Association Study: methods
KW  - Middle Aged
KW  - Neuroimaging: methods
KW  - Risk Factors
KW  - Polymorphism, Single Nucleotide: genetics
LB  - PUB:(DE-HGF)16
C6  - pmid:40830579
C2  - pmc:PMC12815664
DO  - DOI:10.1038/s41380-025-03136-4
UR  - https://pub.dzne.de/record/284046
ER  -