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@ARTICLE{Shen:284046,
      author       = {Shen, Xueyi and Toenders, Yara J and Han, Laura K M and
                      Weihs, Antoine and Alexander, Nina and Andlauer, Till F M
                      and Brosch, Katharina and Forstner, Andreas J and Grotegerd,
                      Dominik and Hahn, Tim and Hermesdorf, Marco and Hosten,
                      Norbert and Jamalabadi, Hamidreza and Meinert, Susanne and
                      Milaneschi, Yuri and Sämann, Philipp G and Stein, Frederike
                      and Stolicyn, Aleks and Teutenberg, Lea and Thng, Gladi and
                      Adams, Mark J and Thomas-Odenthal, Florian and Usemann,
                      Paula and Völker, Uwe and Wittfeld, Katharina and
                      Herrera-Rivero, Marisol and Jiang, Yunxuan and Tian, Chao
                      and Groenewold, Nynke A and Koopowitz, Sheri-Michelle and
                      Strike, Lachlan T and Dannlowski, Udo and Jansen, Andreas
                      and Kircher, Tilo and Nenadić, Igor and Sim, Kang and
                      Straube, Benjamin and Völzke, Henry and Stein, Dan J and
                      Medland, Sarah E and Berger, Klaus and Grabe, Hans and Krug,
                      Axel and McMahon, Katie L and de Zubicaray, Greig and Pozzi,
                      Elena and Veltman, Dick J and Thomopoulos, Sophia I and
                      Jahanshad, Neda and Thompson, Paul M and Schmaal, Lianne and
                      McIntosh, Andrew M and Whalley, Heather C},
      collaboration = {Team, 23andMe Research and group, ENIGMA MDD working},
      othercontributors = {de Zubicaray, Greig},
      title        = {{A}ssociation between polygenic risk for {M}ajor
                      {D}epression and brain structure in a mega-analysis of
                      50,975 participants across 11 studies.},
      journal      = {Molecular psychiatry},
      volume       = {31},
      number       = {2},
      issn         = {1359-4184},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2026-00081},
      pages        = {611 - 621},
      year         = {2026},
      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 (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.},
      keywords     = {Humans / Major Depressive Disorder: genetics / Major
                      Depressive Disorder: pathology / Multifactorial Inheritance:
                      genetics / Male / Female / Genetic Predisposition to
                      Disease: genetics / Brain: pathology / Adult / Magnetic
                      Resonance Imaging: methods / Genome-Wide Association Study:
                      methods / Middle Aged / Neuroimaging: methods / Risk Factors
                      / Polymorphism, Single Nucleotide: genetics},
      cin          = {AG Hoffmann},
      ddc          = {610},
      cid          = {I:(DE-2719)1510600},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40830579},
      pmc          = {pmc:PMC12815664},
      doi          = {10.1038/s41380-025-03136-4},
      url          = {https://pub.dzne.de/record/284046},
}