The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.
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The code to implement the analyses included in the present study is available at https://github.com/zh1peng/paper_code.
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ZC, RBC, JO-G, AM, NS, DP, and SM received support from NIDA grant R01DA047119, awarded to PC and HG. AJ received support from NIH/NIDA T32DA043593. RWW received support for the Neuro-ADAPT study from VICI grant 453.08.01 from the Netherlands Organization for Scientific Research (NWO). RS received funding from NIH grants R01AA013892, P50DA016656, UL1-DE021459 and P30DA024859. LS and DV received funding from the Netherlands Organization for Health Research and Development (ZonMW) grant 31160003 from NWO. LS was also supported by funding from NIH grant R01MH117601. DV received funding from ZonMW grant 31160004 from NWO. AEG and RJH received funding from ZonMW grant 91676084 from NWO. ML and DV received funding from VIDI grant 016.08.322 from NWO, awarded to Ingmar H. A. Franken. AEG received funding for the Cannabis Prospective study from ZonMW grant 31180002 from NWO. JS received funding from R00AA024837. CRL received funding from NIH grants R01AA021449, R01DA023248, R21DA044749, and R21DA045189. Data collection by RM was supported by the Intramural Clinical and Biological Research Program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) funding ZIA-AA000123 (PI: R. Momenan). PT was supported by NIH grants U54 EB020403 from the Big Data to Knowledge (BD2K) program, R01 MH116147, P41 EB015922, and R01 MH111671. NJ was supported by NIH grants R01MH117601, R01AG059874, R01MH121246, P41EB015922, and R01MH116147. We thank the Dougherty Lab at Washington University in St. Louis for sharing the pSI data to facilitate the enrichment analysis. We thank Peter Callas at University of Vermont for offering statistical advice. The IMAGEN study received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant “STRATIFY” (Brain network based stratification of reinforcement-related disorders) (695313), Human Brain Project (HBP SGA 2, 785907, and HBP SGA 3, 945539), the Medical Research Council Grant “c-VEDA” (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute of Health (NIH) (R01DA049238, A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers; and R01MH085772, Axon, Testosterone and Mental Health during Adolescence), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B; Forschungsnetz IMAC-Mind 01GL1745B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: the ANR (ANR-12-SAMA-0004, AAPG2019—GeBra), the Eranet Neuron (AF12-NEUR0008-01—WM2NA; and ANR-18-NEUR00002-01—ADORe), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), U.S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence, the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and King’s College London (KCL). ImagenPathways “Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways” is a collaborative project supported by the European Research Area Network on Illicit Drugs (ERANID). This paper is based on independent research commissioned and funded in England by the National Institute for Health Research (NIHR) Policy Research Programme (project ref. PR-ST-0416-10001). UK Biobank Resource was made available under application #11559 (Enhancing Neuro Imaging Genetics through Meta-Analysis).
TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire. He received conference support or speaker’s fee from Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire and Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien and Oxford University Press. The present work is unrelated to the above grants and relationships. LP served in an advisory or consultancy role for Roche and Viforpharm and received speaker’s fee from Shire. She received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships. RS has served on the scientific advisory board of Embera Neurotherapeutics. The other authors report no biomedical financial interests or potential conflicts of interest. NJ and PT are MPIs of a research grant from Biogen, Inc, for work unrelated to the contents of this manuscript. All other authors have no financial disclosures.
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Cao, Z., Cupertino, R.B., Ottino-Gonzalez, J. et al. Cortical profiles of numerous psychiatric disorders and normal development share a common pattern. Mol Psychiatry 28, 698–709 (2023). https://doi.org/10.1038/s41380-022-01855-6