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A cross-disorder genome-wide association study (GWAS) identified 23 highly pleiotropic single-nucleotide polymorphisms (SNPs) that were associated with at least four neuropsychiatric disorders, and 22 SNPs that were associated predominantly with schizophrenia. Exploring their link to brain-related traits might advance understanding their distinct neurobiological processes. Using the UK Biobank data (<jats:italic>n<\/jats:italic>\u2009=\u200928,952), this study examined the association of both a genetic risk score (GRS) for highly pleiotropic SNPs (PleioPsych-GRS), and a GRS for predominantly schizophrenia-associated SNPs (SCZ-GRS) with 154 measures of subcortical volume, cortical thickness, and surface area as well as 12 outcomes related to mental health. To generate further insights at the individual SNP level, the association between SNPs and brain structure was examined using GWAS summary statistics. The PleioPsych-GRS showed no significant association with brain structure after correction for multiple testing. The SCZ-GRS showed a significant association with an increased surface area of the lateral orbitofrontal region, and an increased volume of the putamen, among others. The PleioPsych-GRS and the SCZ-GRS were associated with eight and four outcomes related to mental health, respectively. Two highly pleiotropic and 10 SCZ-associated SNPs were associated with several structural brain phenotypes. Taken together, these findings indicated that GRSs of highly pleiotropic SNPs and predominantly schizophrenia-associated SNPs have partly distinct associations with brain structure and outcomes related to mental health. Thus, investigating schizophrenia-specific and pleiotropic variants may improve our understanding of the neurobiology of neuropsychiatric disorders.<\/jats:p>","DOI":"10.1038\/s41398-025-03440-1","type":"journal-article","created":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T19:03:01Z","timestamp":1751742181000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurobiological correlates of schizophrenia-specific and highly pleiotropic genetic risk scores for neuropsychiatric disorders"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4500-2175","authenticated-orcid":false,"given":"Lydia M.","family":"Federmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Sindermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-7718","authenticated-orcid":false,"given":"Sabrina","family":"Primus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4087-8259","authenticated-orcid":false,"given":"Federico","family":"Raimondo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7447-2252","authenticated-orcid":false,"given":"Konrad","family":"Oexle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janik","family":"Goltermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3074-599X","authenticated-orcid":false,"given":"Juliane","family":"Winkelmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8770-2464","authenticated-orcid":false,"given":"Markus M.","family":"N\u00f6then","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5828-0867","authenticated-orcid":false,"given":"Katrin","family":"Amunts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6057-5952","authenticated-orcid":false,"given":"Thomas W.","family":"M\u00fchleisen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven","family":"Cichon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon B.","family":"Eickhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7163-3110","authenticated-orcid":false,"given":"Felix","family":"Hoffstaedter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Udo","family":"Dannlowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaustubh R.","family":"Patil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-6368","authenticated-orcid":false,"given":"Andreas J.","family":"Forstner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,5]]},"reference":[{"key":"3440_CR1","doi-asserted-by":"publisher","DOI":"10.1093\/med:psych\/9780198528883.001.0001","volume-title":"Cognitive behavioural processes across psychological disorders: A transdiagnostic approach to research and treatment","author":"AG Harvey","year":"2004","unstructured":"Harvey AG, Watkins E, Mansell W. 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The UKBB study was approved by the North West Multi-centre Research Ethics Committee (MREC, reference number 11\/NW\/0382). All UKBB participants provided written informed consent []. The present study was conducted under UKBB Application Number 41655. The SNP-to-IDP analysis was performed using summary statistics of previous GWAS of structural brain phenotypes from the ENIGMA and CHARGE consortia [\u2013]. These summary statistics did not include any individual-level personal data. The ENIGMA and CHARGE studies were approved by the respective ethics committees and informed consent was obtained for all participants as described in the respective original studies [\u2013].","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Prof. Markus N\u00f6then reported receiving personal fees from Life&Brain GmbH, which were not connected to this work. 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