Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

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Dick Schijven https://orcid.org/0000-0001-5190-7241 , Merel C. Postema , Masaki Fukunaga https://orcid.org/0000-0003-1010-2644 , Jun...

Dick Schijven https://orcid.org/0000-0001-5190-7241, Merel C. Postema, Masaki Fukunaga https://orcid.org/0000-0003-1010-2644, Junya Matsumoto https://orcid.org/0000-0003-4228-3208, Kenichiro Miura, Sonja M. C. de Zwarte, Neeltje E. M. van Haren, Wiepke Cahn, Hilleke E. Hulshoff Pol, René S. Kahn, Rosa Ayesa-Arriola, Víctor Ortiz-García de la Foz https://orcid.org/0000-0002-0627-1827, Diana Tordesillas-Gutierrez https://orcid.org/0000-0003-1458-3932, Javier Vázquez-Bourgon https://orcid.org/0000-0002-5478-3376, Benedicto Crespo-Facorro, Dag Alnæs https://orcid.org/0000-0001-7361-5418, Andreas Dahl, Lars T. Westlye https://orcid.org/0000-0001-8644-956X, Ingrid Agartz, Ole A. Andreassen https://orcid.org/0000-0002-4461-3568, Erik G. Jönsson, Peter Kochunov, Jason M. Bruggemann, Stanley V. Catts, Patricia T. Michie, Bryan J. Mowry, Yann Quidé, Paul E. Rasser https://orcid.org/0000-0003-3482-721X, Ulrich Schall https://orcid.org/0000-0001-9041-4562, Rodney J. Scott https://orcid.org/0000-0001-7724-3404, Vaughan J. Carr, Melissa J. Green, Frans A. Henskens https://orcid.org/0000-0003-2358-5630, Carmel M. Loughland, Christos Pantelis https://orcid.org/0000-0002-9565-0238, Cynthia Shannon Weickert, Thomas W. Weickert, Lieuwe de Haan, Katharina Brosch https://orcid.org/0000-0002-0526-8095, Julia-Katharina Pfarr, Kai G. Ringwald, Frederike Stein, Andreas Jansen, Tilo T. J. Kircher, Igor Nenadić, Bernd Krämer https://orcid.org/0000-0002-1145-9103, Oliver Gruber https://orcid.org/0000-0003-1841-7413, Theodore D. Satterthwaite https://orcid.org/0000-0001-7072-9399, Juan Bustillo, Daniel H. Mathalon, Adrian Preda, Vince D. Calhoun https://orcid.org/0000-0001-9058-0747, Judith M. Ford https://orcid.org/0000-0002-6500-6548, Steven G. Potkin, Jingxu Chen, Yunlong Tan https://orcid.org/0000-0002-3522-3912, Zhiren Wang, Hong Xiang, Fengmei Fan, Fabio Bernardoni, Stefan Ehrlich https://orcid.org/0000-0003-2132-4445, Paola Fuentes-Claramonte https://orcid.org/0000-0002-1428-7976, Maria Angeles Garcia-Leon, Amalia Guerrero-Pedraza, Raymond Salvador https://orcid.org/0000-0001-5557-1562, Salvador Sarró https://orcid.org/0000-0003-1835-2189, Edith Pomarol-Clotet, Valentina Ciullo https://orcid.org/0000-0002-6870-6259, Fabrizio Piras, Daniela Vecchio, Nerisa Banaj, Gianfranco Spalletta https://orcid.org/0000-0002-7432-4249, Stijn Michielse, Therese van Amelsvoort, Erin W. Dickie, Aristotle N. Voineskos https://orcid.org/0000-0003-0156-0395, Kang Sim https://orcid.org/0000-0003-3209-9626, Simone Ciufolini, Paola Dazzan, Robin M. Murray https://orcid.org/0000-0003-0829-0519, Woo-Sung Kim, Young-Chul Chung, Christina Andreou, André Schmidt, Stefan Borgwardt, Andrew M. McIntosh, Heather C. Whalley, Stephen M. Lawrie https://orcid.org/0000-0002-2444-5675, Stefan du Plessis, Hilmar K. Luckhoff, Freda Scheffler https://orcid.org/0000-0002-8898-8599, Robin Emsley, Dominik Grotegerd, Rebekka Lencer, Udo Dannlowski, Jesse T. Edmond, Kelly Rootes-Murdy, Julia M. Stephen, Andrew R. Mayer, Linda A. Antonucci, Leonardo Fazio https://orcid.org/0000-0003-4000-974X, Giulio Pergola https://orcid.org/0000-0002-9193-1841, Alessandro Bertolino, Covadonga M. Díaz-Caneja, Joost Janssen, Noemi G. Lois https://orcid.org/0000-0002-6600-072X, Celso Arango, Alexander S. Tomyshev, Irina Lebedeva, Simon Cervenka, Carl M. Sellgren, Foivos Georgiadis, Matthias Kirschner, Stefan Kaiser, Tomas Hajek, Antonin Skoch https://orcid.org/0000-0002-1739-3256, Filip Spaniel, Minah Kim https://orcid.org/0000-0001-8668-0817, Yoo Bin Kwak, Sanghoon Oh https://orcid.org/0000-0002-7394-5211, Jun Soo Kwon, Anthony James https://orcid.org/0000-0002-2742-8328, Geor Bakker, Christian Knöchel, Michael Stäblein, Viola Oertel, Anne Uhlmann https://orcid.org/0000-0002-1753-7811, Fleur M. Howells, Dan J. Stein https://orcid.org/0000-0001-7218-7810, Henk S. Temmingh https://orcid.org/0000-0002-7688-0759, Ana M. Diaz-Zuluaga, Julian A. Pineda-Zapata, Carlos López-Jaramillo, Stephanie Homan, Ellen Ji, Werner Surbeck, Philipp Homan https://orcid.org/0000-0001-9034-148X, Simon E. Fisher https://orcid.org/0000-0002-3132-1996, Barbara Franke https://orcid.org/0000-0003-4375-6572, David C. Glahn https://orcid.org/0000-0002-4749-6977, Ruben C. Gur https://orcid.org/0000-0002-9657-1996, Ryota Hashimoto, Neda Jahanshad, Eileen Luders https://orcid.org/0000-0001-5659-992X, Sarah E. Medland, Paul M. Thompson https://orcid.org/0000-0002-4720-8867, Jessica A. Turner, Theo G. M. van Erp, and Clyde Francks https://orcid.org/0000-0002-9098-890X [email protected]Authors Info & Affiliations

Edited by Marcus Raichle, Washington University in St Louis School of Medicine, St. Louis, MO; received August 24, 2022; accepted February 3, 2023

March 28, 2023

120 (14) e2213880120

Significance

Schizophrenia has been proposed to involve altered left-hemispheric dominance for language in the brain, but research in limited sample sizes has not clarified whether structural asymmetry differs in this condition. In MRI data from 5,080 affected individuals and 6,015 controls, we found altered asymmetry of two brain regions driven by thinner left-hemisphere cortex in schizophrenia: the rostral anterior cingulate and middle temporal gyrus. The latter is a core region of the left-hemisphere language network. Effects were very small in terms of macroanatomical asymmetry, but might be compatible with altered lateralized function. Across all brain regions considered together, 7% of variance in asymmetry was linked to case–control status, indicating a more diffuse pattern of subtly altered anatomical asymmetry.

Abstract

Left–right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case–control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case–control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case–control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case–control status. Subtle case–control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

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Data, Materials, and Software Availability

This study made use of 46 separate data sets collected around the world, under a variety of different consent procedures and regulatory bodies, during recent decades. Requests to access the data sets will be considered in relation to the relevant consents, rules and regulations, and can be made via the schizophrenia working group of the ENIGMA consortium: http://enigma.ini.usc.edu/ongoing/enigma-schizophrenia-working-group/.

Acknowledgments

The ENIGMA project is in part supported by the National Institute of Biomedical Imaging and Bioengineering of the NIH (U54EB020403). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Individual Funding Sources: D.S., M.C.P., S.E.F., and C.F.: Max Planck Society (Germany). R.A.-A.: Miguel Servet contract from the Carlos III Health Institute (CP18/00003). J.V.-B.: Instituto de Investigación Sanitaria Valdecilla (IDIVAL) (INT/A21/10, INT/A20/04). D.A.: South-Eastern Norway Regional Health Authority (2019107, 2020086). L.T.W.: Research Council of Norway (223273, 300767), South-Eastern Norway Regional Health Authority (2019101), and European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (ERC StG, 802998). O.A.A.: Research Council of Norway (223273, 275054), KG Jebsen Stiftelsen, South East Norway Health Authority (2017-112, 2019-108). P.K.: NIH (R01MH123163, R01EB015611). M.J.G.: National Health and Medical Research Council (NHMRC) (630471, 1051672, 1081603). C.P.: NHMRC Senior Principal Research Fellowship (1105825), NHMRC L3 Investigator Grant (1196508). V.D.C.: NIH (R01MH118695), NSF (2112455). J.M.F.: Senior Research Career Scientist Award, Department of Veterans Affairs. P.F.-C.: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and Instituto de Salud Carlos III, cofunded by European Union (European Regional Development Fund (ERDF)/European Social Fund (ESF), “Investing in your future”): Sara Borrell Research contract (CD19/00149). G.S.: Italian Ministry of Health (RC17-18-19-20-21/A). A.N.V.: National Institute of Mental Health (NIMH), Canadian Institutes of Health Research (CIHR), Canada Foundation for Innovation, Centre for Addiction and Mental Health (CAMH) Foundation, University of Toronto. Y.-C.C.: Korean Mental Health Technology R&D Project (HL19C0015) and Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI18C2383), funded by the Ministry of Health & Welfare, Republic of Korea. J.M.S.: NIH (1P20RR021938-01). A.R.M.: NIH (P30GM122734, R01MH101512). C.M.D.-C.: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI17/00481, PI20/00721, JR19/00024). S. Cervenka: Swedish Research Council (523-2014-3467). M. Kirschner: Swiss National Science Foundation (SNSF) (P2SKP3_178175). T.H.: CIHR (142255), Ministry of Health of the Czech Republic (16-32791A, NU20-04-00393), Brain & Behavior Research Foundation (BBRF) Young and Independent Investigator Awards. A. James: Medical Research Council (MRC) (G0500092). P.H.: NARSAD grant from the BBRF (28445), Research Grant from the Novartis Foundation (20A058). R.C.G.: NIH (1R01MH117014, 1R01MH119219). N.J.: NIH (R01MH117601). S.E.M.: NHMRC (APP1172917). J.A.T.: NIH (R01MH121246). Dataset-Specific Funding Sources and Acknowledgments: AMC: Supported by grants from The Netherlands Organisation for Health Research and Development (ZonMw) (3160007, 91676084, 31160003, 31180002, 31000056, 2812412, 100001002, 100002034), the Dutch Research Council (NWO) (90461193, 40007080, 48004004, 40003330), the Amsterdam Brain Imaging Platform, Neuroscience Campus Amsterdam, and the Dutch Brain Foundation. Processing with FreeSurfer was performed on the Dutch e-Science Grid through BiG Grid project and COMMIT project “e-Biobanking with imaging for healthcare,” which are funded by the NWO. ASRB: Australian Schizophrenia Research Bank, supported by the NHMRC (Enabling Grant, 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. Chief Investigators for ASRB were S.V.C., P.T.M., B.J.M., U.S., R.J.S., V.J.C., F.A.H., C.P., Assen Jablensky. We thank C.M.L., the ASRB Manager, and acknowledge the help of Jason Bridge for ASRB database queries. CAMH: Datasets were collected and shared with support from the CAMH Foundation and the CIHR. CASSI (Cognitive and Affective Symptoms in Schizophrenia Intervention): Supported by the University of New South Wales School of Psychiatry, the NHMRC (568807), Neuroscience Research Australia, the Schizophrenia Research Institute utilizing infrastructure funding from NSW Ministry of Health, the Macquarie Group Foundation, and the ASRB (see above). CIAM (Cortical Inhibition and Attentional Modulation): The CIAM group (PI: F.M.H.) was supported by the University Research Committee, University of Cape Town; South African National Research Foundation (NRF); South African Medical Research Council (SA MRC). CLING (Clinical Neuroscience Goettingen): Sample data collection partially supported by the Deutsche Forschungsgemeinschaft (DFG) (GR1950/5-1 to O.G.). COBRE (Center for Biomedical Research Excellence): Supported by NIH (R01EB006841, P20GM103472, 5R01MH094524 to V.D.C. and J.A.T. R01AA021771 and P50AA022534 to J.M.S.), and the NSF (1539067). EdinburghEHRS: Funded by the MRC (G9226254, G9825423), the Dr. Mortimer and Theresa Sackler Foundation. EdinburghFunc: Funded by the MRC Clinical Training Fellowship (G84/5699) and Health Foundation Clinician Scientist Fellowship (2268/4295). EdinburghSFMH: Funded by an award from the Translational Medicine Research Collaboration (NS_EU_166), Scottish Enterprise, Pfizer, the Dr. Mortimer and Theresa Sackler Foundation. The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336. Is e buidheann carthannais a th’ ann an Oilthigh Dhùn Èideann, clàraichte an Alba, àireamh clàraidh SC005336. EONCKS: Supported by the SA MRC and the New Partnership for Africa’s Development initiative through the Department of Science and Technology of South Africa (#65174). ESO: Supported by the Ministry of Health of the Czech Republic (NU20-04-00393). FBIRN (Function Biomedical Informatics Research Network): Supported by the National Center for Research Resources at the NIH (1 U24 RR021992 (FBIRN) and 1 U24 RR025736-01 (Biomedical Informatics Research Network Coordinating Center; http://www.birncommunity.org)). Data were processed by the UCI High-Performance Computing cluster supported by Joseph Farran (supported by NIMH R01 MH-58262), Harry Mangalam, and Adam Brenner (supported by NIH 5R01 MH61603, 2R01MH058251), and the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH (through grant UL1 TR000153). FBIRN thank Mrs. Liv McMillan for overall study coordination. FOR2107 Marburg: Funded by the DFG, T.T.J.K. (speaker FOR2107; KI588/14-1, KI588/14-2), Axel Krug (KR3822/5-1, KR3822/7-2), I.N. (NE2254/1-2, NE2254/3-1, NE2254/4-1), Carsten Konrad (KO4291/3-1), and A. Jansen (JA1890/7-1, JA1890/7-2). FOR2107 Münster: Funded by the DFG (FOR2107 DA1151/5-1, DA1151/5-2 to U.D.; SFB-TRR58, Projects C09 and Z02 to U.D.) and the Interdisciplinary Center for Clinical Research of the medical faculty of Münster (Dan3/012/17 to U.D.). Frankfurt: MRI was performed at the Frankfurt Brain Imaging Centre, supported by the DFG and the German Ministry for Education and Research (Brain Imaging Center Frankfurt/Main, DLR01GO0203). GAP (Genetics and Psychosis): The GAP dataset represents independent research funded by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre at South London, Maudsley National Health Service (NHS) Foundation Trust, and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. GIPSI: Supported by “PRISMA U.T” Colciencias Invitación 990 del 3 de Agosto de 2017, Código 111577757629, Contrato 781 de 2017. GROUP: We thank Truda Driesen and Inge Crolla for their coordinating roles in the data collection, as well as the G.R.O.U.P. investigators: R.S.K., Don H. Linszen, Jim van Os, Durk Wiersma, Richard Bruggeman, W.C., L.dH., Lydia Krabbendam, Inez Myin-Germeys. Infrastructure for the GROUP study is funded through the Geestkracht programme of ZonMw (10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord; Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical center, The Hague; Maastricht: Maastricht University Medical Centre and the mental health institutions: GGzE, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem; Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht, GGZ Centraal, and Delta). HMS (Homburg Multidiagnosis Study): Sample data collection was supported by a grant of the Competence Network Schizophrenia to O.G. HUBIN (Human Brain Informatics): Supported by the Swedish Research Council (K2015-62X-15077-12-3), 2017-00949, the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, the Knut and Alice Wallenberg Foundation. Huilong: Funded by the National Natural Science Foundation of China (81761128021; 31671145; 81401115; 81401133), Beijing Municipal Science & Technology Commission grant (Z141107002514016), Beijing Natural Science Foundation (7162087), Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding (XMLX201609; zylx201409). IGP: Imaging Genetics in Psychosis study, funded by Project Grants from the NHMRC (APP630471 and APP1081603), and the Macquarie University’s ARC Centre of Excellence in Cognition and its Disorders (CE110001021). This project used participants from the ASRB (see above), using an infrastructure grant from the NSW Ministry of Health. IMH: Supported by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/05028), and the Singapore Bioimaging Consortium (RP C009/2006) awarded to K.S. KaSP: Supported by the Swedish Research Council (K2015-62X-15077-12-3), and by grants from the Swedish Medical Research Council (2009-7053, 2013-2838, 523-2014-3467), the Swedish Brain Foundation, Åhlén-siftelsen, Svenska Läkaresällskapet, Petrus och Augusta Hedlunds Stiftelse, Torsten Söderbergs Stiftelse, the AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science, Söderbergs Königska Stiftelse, Professor Bror Gadelius Minne, Knut och Alice Wallenbergs stiftelse, the Swedish Federal Government under the LUA/ALF agreement (C.M.S., S. Cervenka), Centre for Psychiatry Research, KID-funding from the Karolinska Institutet. Madrid: Supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), cofinanced by ERDF Funds from the European Commission, “A way of making Europe,” CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program (FP7-4-HEALTH-2009-2.2.1-2-241909—Project EU-GEI, FP7-HEALTH-2013-2.2.1-2-603196—Project PSYSCAN, and FP7-HEALTH-2013-2.2.1-2-602478—Project METSY), European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (115916—Project PRISM, and 777394—Project AIMS-2-TRIALS), Fundación Familia Alonso, Fundación Alicia Koplowitz. MCIC: Supported by the NIH (NIH/NCRR P41RR14075, R01EB005846 to V.D.C.), the Department of Energy (DE-FG02- 99ER62764), the Mind Research Network, the Morphometry BIRN (1U24, RR021382A), the Function BIRN (U24RR021992-01, NIH.NCRR MO1 RR025758-01, NIMH 1RC1MH089257 to V.D.C.), the DFG (research fellowship to S.E.), and a NARSAD Young Investigator Award (to S.E.). MPRC: Support received from NIH (U01MH108148, 2R01EB015611, R01MH112180, R01DA027680, R01MH085646, P50MH103222, and T32MH067533), a State of Maryland contract (M00B6400091), and NSF grant (1620457). OLIN: Supported by NIH (R01MH106324, R01MH077945). Osaka: Partially supported by AMED (JP21dm0307002, JP21dm0207069, JP21dk0307103, JP21uk1024002, and JP21wm0425012), JSPS KAKENHI (JP20H03611, JP20K06920), and Intramural Research Grant (3-1) for Neurological and Psychiatric Disorders of NCNP. Computations were performed using Research Center for Computational Science, Okazaki, Japan. Oxford: We would like to thank the participants and their families, referring psychiatrists, and the Donnington Health Centre, Oxford. This study is supported by the MRC, OHSRC, UK EPSRC, BBSRC, and Wellcome Trust. PAFIP: We wish to thank all PAFIP research teams and all patients and family members who participated in the study. PAFIP has been funded by Instituto de Salud Carlos III through the projects PI14/00639, PI14/00918, and PI17/01056 (cofunded by ERDF/ESF “Investing in your future”), Health Research Institute Marques de Valdecilla (NTC0235832, NCT02534363), Instituto de Salud Carlos III, FIS 00/3095, 01/3129, PI020499, PI060507, PI10/00183, the SENY Fundació Research Grant (CI 2005‐0308007), the Fundación Marqués de Valdecilla (API07/011), MINECOSAF2013-46292-R, PSYSCAN (Exp.: HEALTH.2013.2.2.1-2_Grant agreement no. 603196). We want to particularly acknowledge the patients and the BioBankValdecilla (PT13/0010/0024) integrated in the Spanish National Biobanks Network for its collaboration. We thank IDIVAL Neuroimaging Unit for its help in the technical execution of this work. RSCZ: Supported in part by the RFBR (20-013-00748). SCORE: This study was supported in part by the SNSF (3232BO_119382). We thank the FePsy (Frueherkennung von Psychosen; early detection of psychosis) Study Group from the University of Basel, Department of Psychiatry, Switzerland, for the recruitment of the study participants. The FePsy Study was supported in part by grant no. SNF 3200-057216/1, ext./2, ext./3. SNUH: Supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and the Korea Brain Research Institute (KBRI) basic research program through the KBRI, funded by the Ministry of Science, ICT & Future Planning (2019R1C1C1002457, 2020M3E5D9079910, 21-BR-03–01). SWIFT: Supported in part by the SNSF (320030_146789). TOP: Supported by the Research Council of Norway (#160181, 190311, 223273, 213837, 249711), the South-East Norway Health Authority (2014114, 2014097, 2017- 112), the Kristian Gerhard Jebsen Stiftelsen (SKGJ‐MED‐008), and the European Community’s Seventh Framework Programme (FP7/2007–2013), grant agreement no. 602450 (IMAGEMEND). UCISZ: Supported by the NIMH (R21MH097196 to T.G.M.v.E.). Data were processed by the UCI High-Performance Computing cluster (see FBIRN). UMCU: Supported by ZonMw (90802123, 91746370 to H.E.H.P., and 10-000-1001 to R.S.K.). UNIBA: Supported by grant funding from the Italian Ministry of Research (2017M7SZM8_004, PI A.B.; 2017K2NEF4, PI G.P.). UNIMAAS: Supported by ZonMw (91112002) and by a personal grant to T.v.A. (ZonMw-VIDI: 91712394). This clinical trial was registered in the Dutch clinical trial registry under ID: NTR5094 (https://trialsearch.who.int/Trial2.aspx?TrialID=NTR5094). Zurich: Funded by the SNSF.

Author contributions

D.S., M.C.P., S.E.F., B.F., D.C.G., R.C.G., R.H., N.J., E.L., S.E.M., P.M.T., J.A.T., T.G.M.v.E., and C.F. designed research; D.S., M.C.P., M.F., J.M., K.M., S.M.C.d.Z., N.E.M.v.H., W.C., H.E.H.P., R.S.K., R.A.-A., V.O.-G.d.l.F., D.T.-G., J.V.-B., B.C.-F., D.A., A.D., L.T.W., I.A., O.A.A., E.G.J., P.K., J.M.B., S.V.C., P.T.M., B.J.M., Y.Q., P.E.R., U.S., R.J.S., V.J.C., M.J.G., F.A.H., C.M.L., C.P., C.S.W., T.W.W., L.d.H., K.B., J.-K.P., K.G.R., F. Stein, A. Jansen, T.T.J.K., I.N., B.K., O.G., T.D.S., J.B., D.H.M., A.P., V.D.C., J.M.F., S.G.P., J.C., Y.T., Z.W., H.X., F.F., F.B., S.E., P.F.-C., M.A.G.-L., A.G.-P., R.S., S.S., E.P.-C., V.C., F.P., D.V., N.B., G.S., S.M., T.v.A., E.W.D., A.N.V., K.S., S. Ciufolini, P.D., R.M.M., W.-S.K., Y.-C.C., C. Andreou, A. Schmidt, S.B., A.M.M., H.C.W., S.M.L., S.d.P., H.K.L., F. Scheffler, R.E., D.G., R.L., U.D., J.T.E., K.R.-M., J.M.S., A.R.M., L.A.A., L.F., G.P., A.B., C.M.D.-C., J.J., N.G.L., C. Arango, A.S.T., I.L., S. Cervenka, C.M.S., F.G., M. Kirschner, S.K., T.H., A. Skoch, F. Spaniel, M. Kim, Y.B.K., S.O., J.S.K., A. James, G.B., C.K., M.S., V.O., A.U., F.M.H., D.J.S., H.S.T., A.M.D.-Z., J.A.P.-Z., C.L.-J., S.H., E.J., W.S., P.H., D.C.G., R.C.G., R.H., J.A.T., and T.G.M.v.E. performed research; D.S., M.C.P., M.F., J.M., K.M., S.M.C.d.Z., N.E.M.v.H., W.C., H.E.H.P., R.S.K., R.A.-A., V.O.-G.d.l.F., D.T.-G., J.V.-B., B.C.-F., D.A., A.D., L.T.W., I.A., O.A.A., E.G.J., P.K., J.M.B., S.V.C., P.T.M., B.J.M., Y.Q., P.E.R., U.S., R.J.S., V.J.C., M.J.G., F.A.H., C.M.L., C.P., C.S.W., T.W.W., L.d.H., K.B., J.-K.P., K.G.R., F. Stein, A. Jansen, T.T.J.K., I.N., B.K., O.G., T.D.S., J.B., D.H.M., A.P., V.D.C., J.M.F., S.G.P., J.C., Y.T., Z.W., H.X., F.F., F.B., S.E., P.F.-C., M.A.G.-L., A.G.-P., R.S., S.S., E.P.-C., V.C., F.P., D.V., N.B., G.S., S.M., T.v.A., E.W.D., A.N.V., K.S., S. Ciufolini, P.D., R.M.M., W.-S.K., Y.-C.C., C. Andreou, A. Schmidt, S.B., A.M.M., H.C.W., S.M.L., S.d.P., H.K.L., F. Scheffler, R.E., D.G., R.L., U.D., J.T.E., K.R.-M., J.M.S., A.R.M., L.A.A., L.F., G.P., A.B., C.M.D.-C., J.J., N.G.L., C. Arango, A.S.T., I.L., S. Cervenka, C.M.S., F.G., M. Kirschner, S.K., T.H., A. Skoch, F. Spaniel, M. Kim, Y.B.K., S.O., J.S.K., A. James, G.B., C.K., M.S., V.O., A.U., F.M.H., D.J.S., H.S.T., A.M.D.-Z., J.A.P.-Z., C.L.-J., S.H., E.J., W.S., P.H., D.C.G., R.C.G., R.H., J.A.T., and T.G.M.v.E. analyzed data; and D.S. and C.F. wrote the paper.

Competing interests

O.A.A. is a consultant to HealthLytix. J.B. has received royalties from UpToDate. D.H.M. is a consultant for Recognify Life Sciences Inc., and Syndesi Therapeutics. A.B. received consulting fees by Biogen and lecture fees by Otsuka, Janssen, and Lundbeck. C.M.D.-C. has received honoraria from Exeltis and Angelini. C. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda. B.F. has received educational speaking fees from Medice GmbH. S.K. receives royalties for cognitive test and training software from Schuhfried, Austria.

Supporting Information

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences

Vol. 120 | No. 14
April 4, 2023

Classifications

Copyright

Data, Materials, and Software Availability

Submission history

Received: August 24, 2022

Accepted: February 3, 2023

Published online: March 28, 2023

Published in issue: April 4, 2023

Keywords

Schizophrenia
brain imaging
asymmetry
cortical
subcortical

Acknowledgments

Author Contributions

Competing Interests

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands

Merel C. Postema

Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands

Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam 1081 HZ, The Netherlands

Division of Cerebral Integration, National Institute for Physiological Sciences, Okazaki 444-8585, Japan

Department of Pathology of Mental Diseases, National Center of Neurology and Psychiatry, National Institute of Mental Health, Tokyo 187-8551, Japan

Kenichiro Miura

Department of Pathology of Mental Diseases, National Center of Neurology and Psychiatry, National Institute of Mental Health, Tokyo 187-8551, Japan

Sonja M. C. de Zwarte

Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CG, The Netherlands

Neeltje E. M. van Haren

Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CG, The Netherlands

Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center Sophia Children’s Hospital, Rotterdam 3015 CN, The Netherlands

Wiepke Cahn

Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CG, The Netherlands

Hilleke E. Hulshoff Pol

Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CG, The Netherlands

René S. Kahn

Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CG, The Netherlands

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029

The Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, New York, NY 10468

Rosa Ayesa-Arriola

Department of Psychiatry, Instituto de Investigación Marqués de Valdecilla, University Hospital Marqués de Valdecilla, Santander 39008, Spain

Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid 28029, Spain

Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander 39011, Spain

Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid 28029, Spain

Department of Psychiatry, Marqués de Valdecilla University Hospital, Instituto de Investigación Sanitaria Valdecilla, School of Medicine, University of Cantabria, Santander 39011, Spain

Department of Radiology, Instituto de Investigación Marqués de Valdecilla, Marqués de Valdecilla University Hospital, Santander 39011, Spain

Advanced Computing and e-Science, Instituto de Física de Cantabria, Universidad de Cantabria – Consejo Superior de Investigaciones Científicas, Santander 39005, Spain

Department of Psychiatry, Instituto de Investigación Marqués de Valdecilla, University Hospital Marqués de Valdecilla, Santander 39008, Spain

Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid 28029, Spain

Benedicto Crespo-Facorro

Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid 28029, Spain

Department of Psychiatry, School of Medicine, University of Sevilla, University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas – Instituto de Biomedicina de Sevilla, Sevilla 41013, Spain

Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo 0450, Norway

Department of Psychology, University of Oslo, Oslo 0373, Norway

Bjørknes College, Oslo 0456, Norway

Andreas Dahl

Department of Psychology, University of Oslo, Oslo 0373, Norway

Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo 0450, Norway

Department of Psychology, University of Oslo, Oslo 0373, Norway

Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0372, Norway

KG Jebsen Center for Neurodevelopmental Disorders, University of Oslo, Oslo 0450, Norway

Ingrid Agartz

Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo 0450, Norway

Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo 0373, Norway

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Stockholm 113 64, Sweden

Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo 0450, Norway

Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0372, Norway

Erik G. Jönsson

Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo 0450, Norway

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Stockholm 113 64, Sweden

Peter Kochunov

Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201

Jason M. Bruggemann

School of Psychiatry, University of New South Wales, Sydney 2033, Australia

Neuroscience Research Australia, Sydney 2031, Australia

Edith Collins Centre (Translational Research in Alcohol, Drugs & Toxicology), Sydney Local Health District, Sydney 2050, Australia

Specialty of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia

Stanley V. Catts

School of Medicine, The University of Queensland, Brisbane 4006, Australia

Patricia T. Michie

School of Psychological Sciences, University of Newcastle, Newcastle 2308, Australia

Bryan J. Mowry

Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia

Queensland Centre for Mental Health Research, The University of Queensland, Brisbane 4076, Australia

Yann Quidé

School of Psychiatry, University of New South Wales, Sydney 2033, Australia

Neuroscience Research Australia, Sydney 2031, Australia

Centre for Brain and Mental Health Research, University of Newcastle, Newcastle 2308, Australia

Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Newcastle 2308, Australia

Hunter Medical Research Institute, Newcastle 2305, Australia

Centre for Brain and Mental Health Research, University of Newcastle, Newcastle 2308, Australia

School of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle 2308, Australia

Vaughan J. Carr

School of Psychiatry, University of New South Wales, Sydney 2033, Australia

Neuroscience Research Australia, Sydney 2031, Australia

Melissa J. Green

School of Psychiatry, University of New South Wales, Sydney 2033, Australia

Neuroscience Research Australia, Sydney 2031, Australia

School of Medicine and Public Health, University of Newcastle, Newcastle 2308, Australia

PRC for Health Behaviour, Hunter Medical Research Institute, Newcastle 2305, Australia

Carmel M. Loughland

School of Medicine and Public Health, University of Newcastle, Newcastle 2308, Australia

Hunter New England Mental Health Service, Newcastle 2305, Australia

Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne 3053, Australia

Cynthia Shannon Weickert

School of Psychiatry, University of New South Wales, Sydney 2033, Australia

Neuroscience Research Australia, Sydney 2031, Australia

Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY 13210

Thomas W. Weickert

School of Psychiatry, University of New South Wales, Sydney 2033, Australia

Neuroscience Research Australia, Sydney 2031, Australia

Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY 13210

Lieuwe de Haan

Early Psychosis Department, Department of Psychiatry, Amsterdam UMC (location AMC), Amsterdam 1105 AZ, The Netherlands

Arkin Institute for Mental Health, Amsterdam 1033 NN, The Netherlands