{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:25:35Z","timestamp":1791926735863,"version":"4.3.4"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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 (\u03b2\n                    <jats:sub>ICV<\/jats:sub>\n                    \u2009=\u2009\u22120.017, p\n                    <jats:sub>ICV<\/jats:sub>\n                    \u2009=\u20091.97\u2009\u00d7\u200910\n                    <jats:sup>\u22126<\/jats:sup>\n                    ; \u03b2\n                    <jats:sub>Surf<\/jats:sub>\n                    \u2009=\u2009\u22120.013, p\n                    <jats:sub>Surf<\/jats:sub>\n                    \u2009=\u20094.5\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ; pFDR\u2009&lt;\u20093.62\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ). The most significant cortical association was observed in the surface area of the frontal lobe (\u03b2\u2009=\u2009\u22120.011,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20092.85\u2009\u00d7\u200910\n                    <jats:sup>\u22126<\/jats:sup>\n                    , pFDR\u2009=\u20091.42\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    ), particularly in the left medial orbito-frontal gyrus (\u03b2\u2009=\u2009\u22120.021,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20099.48\u2009\u00d7\u200910\n                    <jats:sup>\u22128<\/jats:sup>\n                    , pFDR\u2009=\u20091.25\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    ). In subcortical regions, lower volumes of the thalamus, hippocampus, and pallidum correlated with higher PRS of MD (\u03b2 ranged from \u22120.011 to \u22120.015, p ranged from 0.002\u20131.73\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    , pFDR\u2009&lt;\u20090.006). In a subsample of young individuals only (&lt;25 years old,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u20095570), 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\u2009=\u20097.56\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ). Subsequent Mendelian randomisation analysis revealed potentially causal effects of smaller left hippocampal volume on higher liability for MD (Inverse variance weighted analysis \u03b2\u2009=\u2009\u22120.064,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20098.04\u2009\u00d7\u200910\n                    <jats:sup>\u22123<\/jats:sup>\n                    , pFDR\u2009=\u20090.04). 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.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03136-4","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T17:13:40Z","timestamp":1755623620000},"page":"611-621","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0538-4774","authenticated-orcid":false,"given":"Xueyi","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4117-1143","authenticated-orcid":false,"given":"Yara J.","family":"Toenders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9647-3723","authenticated-orcid":false,"given":"Laura K. 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Dr. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L\u2019Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. Hans J. Grabe has received travel grants and speakers\u2019 honoraria from Neuraxpharm, Servier, Indorsia and Janssen Cilag. PMT received partial research support from Biogen, Inc., for research unrelated to this manuscript. No other authors have conflict of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was approved by the NHS Tayside Research Ethics committee (05\/s1401\/89). Written consents were obtained from all participants from each individual ENIGMA cohort and publicly available datasets. All analyses and interpretation were performed under the guidance of the World Medical Association\u2019s Declaration of Helsinki (\n                      \n                      ). The use, sharing and anonymisation for genetic and neuroimaging data were conducted under the EU General Data Protection Regulation (\n                      \n                      ). Analyses and data management followed the guidelines of the UK Medical Research Council\u2019s \u2018Research, GDPR & Confidentiality\u2019 training. Access to UK Biobank individual-level was obtained under the application #4844. The ABCD study was approved by the National Institute of Mental Health Data Archive, United States (NIMH), and data was accessed through the NDA data base (Federal-Wide Assurance: FWA00018101).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}