Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies
Year: 2025
Type: review
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.
Source: Molecular Psychiatry
Authors: 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 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
Institutions: University of Edinburgh, Erasmus University Rotterdam, The University of Melbourne, Orygen, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Universitätsmedizin Greifswald, German Center for Neurodegenerative Diseases, Philipps University of Marburg, TUM Klinikum, Technical University of Munich, University of Bonn, Forschungszentrum Jülich, University Hospital Bonn, University of Münster, Amsterdam Neuroscience, Amsterdam Public Health, Max Planck Institute of Psychiatry, 23andMe (United States), University of Cape Town, QIMR Berghofer Medical Research Institute, National University of Singapore, Nanyang Technological University, Institute of Mental Health, South African Medical Research Council, Queensland University of Technology, Amsterdam UMC Location University of Amsterdam, University of Southern California
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: Wellcome Trust, Scottish Government, UK Research and Innovation, Scottish Funding Council, Deutsche Forschungsgemeinschaft, Erasmus Universiteit Rotterdam, Technische Universiteit Delft, Bundesministerium für Bildung und Forschung, Erasmus Medisch Centrum, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Max-Planck-Gesellschaft, National Institutes of Health, Chief Scientist Office, Scottish Government Health and Social Care Directorate, Medical Research Council, National Health and Medical Research Council, National Institute of Mental Health, National Institute of Biomedical Imaging and Bioengineering, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1237346504, Verbundprojekt: Nationales Genomforschungsnetz 2 - Genomnetz NeuroNet: Identifizierung von Kandidatengenen für unipolare Depression und Einfluss des CRH/CRH-R1-Signalweges auf die Alkoholabhängigkeit, Brain imaging study of twins, G1438067556, G179444772, G1845387239, G1997327697, G2149946624, G222496000, G238323396, G2437620908, G2511155013, Genetic influences on the brain: A twin imaging study, G2579491456, G259633682, G2765710678, G2831939486, G2928399749, Exploiting genomic approaches to identify the environmental basis of depression, G2985766253, G3138944228, Generation Scotland:NextGenScot, G3265249946, G3377182240, G3434867832, G3506393344, CHECKPOINT: Finding immune & metabolic pathways to SMI, Generation Scotland:NextGenScot, G3762292575, G377074410, G3934624715, G398641320, Exploiting genomic approaches to identify the environmental basis of depression, G4059666690, G4072471859, Die bidirektionale Analyse der Beziehung zwischen subklinischer Arteriosklerose und der Depression (BiDirect), G4280434479, Stratifying Resilience and Depression Longitudinally (STRADL), G4588023527, G470186339, G4730086124, G4812287033, G5052612295, Mental Health Platform Coordinating Centre, G5275296542, G5277938394, G5417235735, Genetics of brain structure and function, G5885064267, G595280944, ENIGMA Center for Worldwide Medicine, Imaging & Genomics, Stratifying Resilience and Depression Longitudinally (STRADL), G6328387595, Identifying clinically relevant neurobiological markers of depression and suicidal behaviours, G6488228673, G648958512, G6514973502, G65769418, G6711686236, G6733821374, G7051567, Analyse der Beziehung zwischen subklinischer Arteriosklerose und der Depression (BiDirect) (Anschlussvorhaben), G7304791810, G7341669135, G7400438497, G7445694801, G7578079922, G75805579, G778464899, G8045000093, G8087705, G8240382675, G839044655, G8584176318, G8600254050, G8724570043, Global studies into the Genetic Architecture of the Brain's White Matter Network through Harmonized and Coordinated Analyses in the ENIGMA-Consortium, Neurobiologically-Based Subtyping of Multi-Cohort Samples with MDD and PTSD Symptoms, ENIGMA Bipolar Initiative: A Global Study of Imaging Genomics & Clinical Outcomes, G961545024
OpenAlex ID: W4413324022