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

作者：Xueyi Shen, Yara J. Toenders, Laura K. M. Han, Antoine Weihs, Nina Alexander, Till F. M. Andlauer, Katharina Brosch, Andreas J. Forstner, Dominik Grotegerd, Tim Hahn, Marco Hermesdorf, Norbert Hosten, Hamidreza Jamalabadi, Susanne Meinert, Yuri Milaneschi, Philipp G. Sämann, Frederike Stein, Aleks Stolicyn, Lea Teutenberg, Gladi Thng, Mark J. Adams, Florian Thomas‐Odenthal, Paula Usemann, Uwe Völker, Katharina Wittfeld, Marisol Herrera-Rivero, Yunxuan Jiang, Chao Tian, Nynke A. Groenewold, Sheri‐Michelle Koopowitz, Lachlan T. Strike, Udo Dannlowski, Andreas Jansen, Tilo Kircher, Igor Nenadić, Kang Sim, Benjamin Straube, Henry Völzke, Dan J. Stein, Sarah E. Medland, Klaus Berger, Hans J. Grabe, Axel Krug, Katie L. McMahon, Greig I. de Zubicaray, Elena Pozzi, Dick J. Veltman, Sophia I. Thomopoulos, Neda Jahanshad, Paul M. Thompson, Lianne Schmaal, Andrew M. McIntosh, Heather C. Whalley, for the ENIGMA MDD working group, Greig de Zubicaray · 发表于：Molecular Psychiatry · 年份：2025 · DOI：10.1038/s41380-025-03136-4 · 被引用次数：4 · 研究领域：Health, Environment, Cognitive Aging、Mental Health Research Topics、Cognitive Abilities and Testing

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 ...