@article {Kocak2025.04.29.25326656,
	author = {Kocak, Ersoy and Naamanka, Joonas and Gradinger, Tobias and Klaassen, Fiona and Nitsche, Johannes and Grotehusmann, Philipp and Adorjan, Kristina and Antonucci, Linda A and Blasi, Giuseppe and Budde, Monika and Di Palo, Piergiuseppe and Heilbronner, Maria and Kikidis, Gianluca C and Navarro-Flores, Alba and Kohshour, Mojtaba Oraki and Papiol, Sergi and Raio, Alessandra and Rampino, Antonio and Reich-Erkelenz, Daniela and Schulte, Eva C. and Senner, Fanny and Sportelli, Leonardo and FinnGen and Bertolino, Alessandro and Falkai, Peter and Heilbronner, Urs and Pergola, Giulio and Schulze, Thomas G. and Meyer-Lindenberg, Andreas and Streit, Fabian and Schwarz, Emanuel},
	title = {Development and validation of genomic biotypes for schizophrenia susceptibility from multiple polygenic scores},
	elocation-id = {2025.04.29.25326656},
	year = {2025},
	doi = {10.1101/2025.04.29.25326656},
	publisher = {Cold Spring Harbor Laboratory Press},
	abstract = {Understanding the genetic architecture of schizophrenia (SCZ) is invaluable for the development of personalized treatment. In three independent cohorts, using an automated pipeline, we calculated 413 psychiatry-relevant polygenic scores. Using these scores, machine learning was applied to stratify SCZ patients into two biotypes in FinnGen (nSCZ=7486), and to validate these results in the PsyCourse Study (nSCZ=421) and Bari (nSCZ=531). While the two biotypes showed comparable polygenic SCZ risk, they were primarily distinguished by a greater predisposition for neuroticism, depression-related traits, and lower cognitive performance in Biotype 1. The genetic prediction of Biotype 1 was phenotypically characterized by an increased prevalence of SCZ and a more severe and complex clinical manifestation. This illustrates that the penetrance of genetic SCZ risk might partially depend on the predisposition for the aforementioned traits through pleiotropic variants. Our results provide novel, replicable insights into the genetic architecture of SCZ and might inform future personalized treatments.Competing Interest StatementGiuseppe Blasi has received lecture and consultant fees by Lundbeck. Antonio Rampino has received lecture fees by Janssen. Alessandro Bertolino received consulting fees from Biogen and lecture fees from Otsuka, Janssen, and Lundbeck. Giulio Pergola has received lecture fees by Lundbeck. Andreas Meyer-Lindenberg has received consultant fees from: Agence Nationale de la Recherche, Brain Mind Institute, Brainsway, CISSN (Catania International Summer School of Neuroscience), Daimler und Benz Stiftung, Fondation FondaMental, Hector Stiftung II, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, MedinCell, Sage Therapeutics, Techspert.io, The LOOP Zuerich, University Medical Center Utrecht, von Behring Roentgen Stiftung. Andreas Meyer-Lindenberg has received speaker fees from: Aerztekammer Nordrhein, BAG Psychiatrie Oberbayern, Biotest AG, Forum Werkstatt Karlsruhe, International Society of Psychiatric Genetics, Brentwood, Klinik fuer Psychiatrie und Psychotherapie Ingolstadt, Lundbeck SAS France, med Update GmbH, Merz-Stiftung, Siemens Healthineers, Society of Biological Psychiatry. Andreas Meyer-Lindenberg has received editorial fees from: American Association for the Advancement of Science, Elsevier, Thieme Verlag. Emanuel Schwarz received speaker fees from bfd buchholz-fachinformationsdienst GmbH and Lundbeckfonden as well as editorial fees from Lundbeckfonden and the Wellcome Trust. The other authors have declared that there are no conflicts of interest in relation to the subject of this study.Funding StatementThis work was supported by the Hector foundation II, the German Federal Ministry of Education and Research (BEST project, grant 01EK2101B), the German Research Foundation (DFG) (TRR 265/2 TP A06), and was endorsed by German Center for Mental Health (DZPG). U.H. was supported by European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (PSY-PGx, grant agreement No 945151) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project number 514201724). T.G.S. was supported by the European Union Horizon 2020 Research and Innovation Program (PSY-PGx, grant agreement No 945151), and also by the Deutsche Forschungsgemeinschaft within the framework of the projects www.kfo241.de and www.PsyCourse.de [SCHU 1603/4-1, 5-1, 7-1]. T.G.S. was further supported by the Dr Lisa Oehler Foundation (Kassel, Germany), the Bundesministerium fuer Bildung und Forschung (BMBF, Federal Ministry of Education and Research; projects: IntegraMent [01ZX1614K], BipoLife [01EE1404H], e:Med Program [01ZX1614K]) and European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (ERA-NET Neuron Projects GEPI-BIOPSY [BMBF No 01EW2005] and MulioBio [BMBF No 01EW2009]). G.C.K.{\textquoteright}s PhD scholarship is financially supported by Exprivia S.p.A. under the Italian ministerial decree D.M. 351. Furthermore, this study was supported by FAIR - Future AI Research (PE00000013), spoke 6 - Symbiotic AI, under the NRRP MUR program funded by the NextGenerationEU; Project CUP : H97G22000210007, and the Apulian regional government for the project: "Early Identification of Psychosis Risk"Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics Committee II of the University of Heidelberg Medical Faculty Mannheim gave ethical approval for this work (protocol no. 2024-845). FinnGen was approved by the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS), and patients and control subjects provided informed consent for biobank research, based on the Finnish Biobank Act. Bari Protocols and procedures were approved by the ethics committee of the University of Bari Aldo Moro. PsyCourse project was approved by the Ethics Committee of the University Medical Center Goettingen. Some clinical centers were teaching hospitals of the University Medical Center Goettingen, and were thus covered by this initial approval. For those clinical sites that were not covered, additional approval from the respective Ethics Committees were obtained. For all centers, these were (clinical centers in parentheses): Ethics Committees of the University Medical Center Goettingen (UMG Goettingen, Bad Zwischenahn, Eschwege, Asklepios Specialized Hospital Goettingen, Hildesheim, Lueneburg, Liebenburg, Osnabrueck, Rotenburg, Tiefenbrunn, Wilhemshaven), Medical Faculty of the LMU Munich (Munich and Augsburg), Medical Faculty of the RU Bochum (Bochum), Medical Association Bremen (Bremen Ost), Medical University of Graz (Graz), Ulm University (Guenzburg) and Medical Association Westfalen-Lippe and Medical Faculty University of Muenster (Muenster).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesFor FinnGen, researchers can apply for health data from the Finnish Data Authority Findata (https://findata.fi/en/permits/) and individual-level genotype data available through the Fingenious portal (https://site.fingenious.fi/en/). These resources are hosted by the Finnish Biobank Cooperative FINBB (https://finbb.fi/en/). Access can only be provided for research projects within the scope of the Finnish Biobank Act, which includes health promotion, understanding disease mechanisms or developing medical products or treatment practices. PsyCourse data is available to bona fide reseachers upon a submission and approval of a research proposal. Individual genotype and clinical data from the University of Bari Aldo Moro with demographic and behavioral characteristics cannot be shared at individual level in raw format because of ethic restrictions. http://www.psycourse.de/openscience-de.html https://docs.finngen.fi/},
	URL = {https://www.medrxiv.org/content/early/2025/04/30/2025.04.29.25326656},
	eprint = {https://www.medrxiv.org/content/early/2025/04/30/2025.04.29.25326656.full.pdf},
	journal = {medRxiv}
}