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Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study

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Matthias Kirschner, Benazir Hodzic-Santor, Mathilde Antoniades, Igor Nenadic, Tilo Kircher, Axel Krug, Tina Meller, Dominik Grotegerd, Alex Fornito, Aurina Arnatkeviciute, Mark A. Bellgrove, Jeggan Tiego, Udo Dannlowski, Katharina Koch, Carina Hülsmann, Harald Kugel, Verena Enneking, Melissa Klug, Elisabeth J. Leehr, Joscha Böhnlein & 46 more Marius Gruber, David Mehler, Pamela DeRosse, Ashley Moyett, Bernhard T. Baune, Melissa Green, Yann Quidé, Christos Pantelis, Raymond Chan, Yi Wang, Ulrich Ettinger, Martin Debbané, Melodie Derome, Christian Gaser, Bianca Besteher, Kelly Diederen, Tom J. Spencer, Paul Fletcher, Wulf Rössler, Lukasz Smigielski, Veena Kumari, Preethi Premkumar, Haeme R.P. Park, Kristina Wiebels, Imke Lemmers-Jansen, James Gilleen, Paul Allen, Petya Kozhuharova, Jan Bernard Marsman, Irina Lebedeva, Alexander Tomyshev, Anna Mukhorina, Stefan Kaiser, Anne Kathrin Fett, Iris Sommer, Sanne Schuite-Koops, Casey Paquola, Sara Larivière, Boris Bernhardt, Alain Dagher, Phillip Grant, Theo G.M. van Erp, Jessica A. Turner, Paul M. Thompson, André Aleman, Gemma Modinos

Original languageEnglish
JournalMolecular Psychiatry
Early online date27 Oct 2021
Accepted/In press2021
E-pub ahead of print27 Oct 2021

Bibliographical note

Funding Information: PMT received partial grant support from Biogen, Inc. (Boston, USA) for work unrelated to this paper. SK received speaker honoraria from Janssen, Takeda, Lundbeck and Roche. Royalties for cognitive test and training software from Schuhfried. In the past 3 years, CP served on an advisory board for Lundbeck, Australia Pty Ltd. He has received honoraria for talks presented at educational meetings organized by Lundbeck. No other disclosures were reported. Funding Information: 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]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MK acknowledges funding from the Swiss National Science Foundation (P2SKP3_178175). Acknowledgments and funding details for the various participating data contributors are listed in at the end of the Supplementary Material. Publisher Copyright: © 2021, The Author(s).

King's Authors


Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12–68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = −0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, pspin = 0.006), BD (rho = −0.672, pspin = 0.009), and MDD (rho = −0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

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