Multiscale characterization of cortical signatures in positive and negative schizotypy: A worldwide ENIGMA study

Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2,730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them to disorder-specific, micro-architectural, connectome, and neurotransmitter-level measures. Positive and negative schizotypy were associated with thinner frontal and thicker paralimbic cortical areas, respectively, and were differentially linked to cortical patterns of schizophrenia-spectrum and neurodevelopmental conditions. Furthermore, these schizotypal cortical patterns mapped onto local attributes of gene expression, cortical myelination, D1 and histamine receptor distributions. Network models identified cortical hub vulnerability to schizotypy-related thickness reduction and epicenters in sensorimotor-to-association and paralimbic areas. This study yields insights into the complex cortical signatures of schizotypy and their relationship to diverse features of cortical organization. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Core funding for ENIGMA was provided by the NIH Big Data to Knowledge (BD2K) program under consortium grant U54 EB020403 (PI: PMT). This research was funded in whole, or in part, by the Wellcome Trust [Sir Henry Dale Fellowship 202397/Z/16/Z to GM]. MK acknowledges funding from the Swiss National Science Foundation (P2SKP3_178175). SL acknowledges funding from the Canadian Institutes of Health Research (CIHR). JYH acknowledges support from the Helmholtz International BigBrain Analytics & Learning Laboratory, and the Natural Sciences and Engineering Research Council of Canada. ML acknowledges funding from the NIH (R01MH129636) Acknowledgments and funding details for the various participating data contributors are listed in at the end of the Supplementary Material. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Each study sample was collected with participants written informed consent approved by local Institutional Review Boards (IRB). The details of the IRB/oversight body that provided approval or exemption for the research described are given below. Ethical approval was given by the following boards/committees: Institute of Psychiatry Research Ethics Committee at King's College London, Institutional Review Board of University of Muenster, Institutional Review Board of Chinese Academy of Sciences, Institutional Review Board of Monash University Institutional Review Board of Philipps-University Marburg, Institutional Review Board of University of Bonn, Institutional Review Board of University of London, Institutional Review Board of University of Geneva, Institutional Review Board of University of Auckland, Ethics Committee of the Mental Health Research Center, Moscow, Institutional Review Board of McGill University, Institutional Review Board of University of Roehampton, Institutional Review Board of Jena University Hospital, Institutional Review Board of Donald and Barbara Zucker School of Medicine at Hofstra University/Northwell, Institutional Review Board of University of Amsterdam, Ethic Commission Zurich, Institutional Review Board of Brunel University London,Institutional Review Board of University of Utrecht, Institutional Review Board of University of Groningen, Research Ethic Committee of Institut Mondor de Recherche Biomedicale Paris, Human Research Ethics Committee at University of Melbourne. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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. Yes I 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors