Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2023

Open Access 01-12-2023 | Research article

Cortical structural changes of morphometric similarity network in early-onset schizophrenia correlate with specific transcriptional expression patterns

Authors: Guanqun Yao, Ting Zou, Jing Luo, Shuang Hu, Langxiong Yang, Jing Li, Xinrong Li, Yuqi Zhang, Kun Feng, Yong Xu, Pozi Liu

Published in: BMC Medicine | Issue 1/2023

Login to get access

Abstract

Background

This study aimed to investigate the neuroanatomical subtypes among early-onset schizophrenia (EOS) patients by exploring the association between structural alterations and molecular mechanisms using a combined analysis of morphometric similarity network (MSN) changes and specific transcriptional expression patterns.

Methods

We recruited 206 subjects aged 7 to 17 years, including 100 EOS patients and 106 healthy controls (HC). Heterogeneity through discriminant analysis (HYDRA) was used to identify the EOS subtypes within the MSN strength. The differences in morphometric similarity between each EOS subtype and HC were compared. Furthermore, we examined the link between morphometric changes and brain-wide gene expression in different EOS subtypes using partial least squares regression (PLS) weight mapping, evaluated genetic commonalities with psychiatric disorders, identified functional enrichments of PLS-weighted genes, and assessed cellular transcriptional signatures.

Results

Two distinct MSN-based EOS subtypes were identified, each exhibiting different abnormal MSN strength and cognitive functions compared to HC. The PLS1 score mapping demonstrated anterior–posterior gradients of gene expression in EOS1, whereas inverse distributions were observed in EOS2 cohorts. Genetic commonalities were identified in autistic disorder and adult schizophrenia with EOS1 and inflammatory bowel diseases with EOS2 cohorts. The EOS1 PLS1- genes (Z < -5) were significantly enriched in synaptic signaling-related functions, whereas EOS2 demonstrated enrichments in virtual infection-related pathways. Furthermore, the majority of observed associations with EOS1-specific MSN strength differences contributed to specific transcriptional changes in astrocytes and neurons.

Conclusions

The findings of this study provide a comprehensive analysis of neuroanatomical subtypes in EOS, shedding light on the intricate relationships between macrostructural and molecular aspects of the EOS disease.
Appendix
Available only for authorised users
Literature
1.
Battle DE. Diagnostic and Statistical Manual of mental disorders (DSM). Codas. 2013;25(2):191–2.PubMed
2.
Alnæs D, Kaufmann T, van der Meer D, Córdova-Palomera A, Rokicki J, Moberget T, et al. Brain heterogeneity in schizophrenia and its association with polygenic risk. JAMA Psychiat. 2019;76(7):739–48.CrossRef
3.
Rhinewine JP, Lencz T, Thaden EP, Cervellione KL, Burdick KE, Henderson I, et al. Neurocognitive profile in adolescents with early-onset schizophrenia: clinical correlates. Biol Psychiatry. 2005;58(9):705–12.PubMedCrossRef
4.
Austin SF, Mors O, Budtz-Jorgensen E, Secher RG, Hjorthoj CR, Bertelsen M, et al. Long-term trajectories of positive and negative symptoms in first episode psychosis: a 10year follow-up study in the OPUS cohort. Schizophr Res. 2015;168(1–2):84–91.PubMedCrossRef
5.
Tamnes CK, Agartz I. White matter microstructure in early-onset schizophrenia: a systematic review of diffusion tensor imaging studies. J Am Acad Child Adolesc Psychiatry. 2016;55(4):269–79.PubMedCrossRef
6.
Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. 2000;157(1):16–25.PubMedCrossRef
7.
Jiang L, Xu Y, Zhu XT, Yang Z, Li HJ, Zuo XN. Local-to-remote cortical connectivity in early- and adulthood-onset schizophrenia. Transl Psychiatry. 2015;5(5): e566.PubMedPubMedCentralCrossRef
8.
Berman RA, Gotts SJ, McAdams HM, Greenstein D, Lalonde F, Clasen L, et al. Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhood-onset schizophrenia. Brain. 2016;139(Pt 1):276–91.PubMedCrossRef
9.
Li Q, Liu S, Cao X, Li Z, Fan YS, Wang Y, et al. Disassociated and concurrent structural and functional abnormalities in the drug-naïve first-episode early onset schizophrenia. Brain Imaging Behav. 2022;16(4):1627–35.PubMedPubMedCentralCrossRef
10.
Fan YS, Xu Y, Li Q, Chen Y, Guo X, Yang S, et al. Systematically mapping gray matter abnormal patterns in drug-naive first-episode schizophrenia from childhood to adolescence. Cereb Cortex. 2023;33(4):1452–61.PubMedCrossRef
11.
Jiang Y, Wang J, Zhou E, Palaniyappan L, Luo C, Ji G, et al. Neuroimaging biomarkers define neurophysiological subtypes with distinct trajectories in schizophrenia. Nature Mental Health. 2023;1(3):186–99.CrossRef
12.
Chand GB, Dwyer DB, Erus G, Sotiras A, Varol E, Srinivasan D, et al. Two distinct neuroanatomical subtypes of schizophrenia revealed using machine learning. Brain. 2020;143(3):1027–38.PubMedPubMedCentralCrossRef
13.
Seidlitz J, Váša F, Shinn M, Romero-Garcia R, Whitaker KJ, Vértes PE, et al. Morphometric similarity networks detect microscale cortical organization and predict inter-individual cognitive variation. Neuron. 2018;97(1):231-47.e7.PubMedCrossRef
14.
Seidlitz J, Nadig A, Liu S, Bethlehem RAI, Vértes PE, Morgan SE, et al. Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders. Nat Commun. 2020;11(1):3358.PubMedPubMedCentralCrossRef
15.
Varol E, Sotiras A, Davatzikos C. HYDRA: Revealing heterogeneity of imaging and genetic patterns through a multiple max-margin discriminative analysis framework. Neuroimage. 2017;145(Pt B):346–64.PubMedCrossRef
16.
17.
Arnatkeviciute A, Fulcher BD, Bellgrove MA, Fornito A. Where the genome meets the connectome: understanding how genes shape human brain connectivity. Neuroimage. 2021;244: 118570.PubMedCrossRef
18.
Fornito A, Arnatkeviciute A, Fulcher BD. Bridging the gap between connectome and transcriptome. Trends Cogn Sci. 2019;23(1):34–50.PubMedCrossRef
19.
Li J, Seidlitz J, Suckling J, Fan F, Ji GJ, Meng Y, et al. Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures. Nat Commun. 2021;12(1):1647.PubMedPubMedCentralCrossRef
20.
Morgan SE, Seidlitz J, Whitaker KJ, Romero-Garcia R, Clifton NE, Scarpazza C, et al. Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes. Proc Natl Acad Sci U S A. 2019;116(19):9604–9.PubMedPubMedCentralCrossRef
21.
Romero-Garcia R, Warrier V, Bullmore ET, Baron-Cohen S, Bethlehem RAI. Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism. Mol Psychiatry. 2019;24(7):1053–64.PubMedCrossRef
22.
Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, et al. A non-D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med. 2020;382(16):1497–506.PubMedCrossRef
23.
Li D, Jin Y, Vandenberg SG, Zhu YM, Tang CH. Report on Shanghai norms for the Chinese translation of the Wechsler Intelligence scale for children-revised. Psychol Rep. 1990;67(2):531–41.PubMedCrossRef
24.
25.
Monereo-Sánchez J, de Jong JJA, Drenthen GS, Beran M, Backes WH, Stehouwer CDA, et al. Quality control strategies for brain MRI segmentation and parcellation: Practical approaches and recommendations - insights from the Maastricht study. Neuroimage. 2021;237: 118174.PubMedCrossRef
26.
Varol E, Sotiras A, Davatzikos C. MIDAS: Regionally linear multivariate discriminative statistical mapping. Neuroimage. 2018;174:111–26.PubMedCrossRef
27.
Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489(7416):391–9.PubMedPubMedCentralCrossRef
28.
Markello RD, Arnatkeviciute A, Poline JB, Fulcher BD, Fornito A, Misic B. Standardizing workflows in imaging transcriptomics with the abagen toolbox. Elife. 2021;10:e72129.PubMedPubMedCentralCrossRef
29.
Arnatkeviciute A, Fulcher BD, Fornito A. A practical guide to linking brain-wide gene expression and neuroimaging data. Neuroimage. 2019;189:353–67.PubMedCrossRef
30.
Abdi H, Williams LJ. Partial least squares methods: partial least squares correlation and partial least square regression. Methods Mol Biol. 2013;930:549–79.PubMedCrossRef
31.
Váša F, Seidlitz J, Romero-Garcia R, Whitaker KJ, Rosenthal G, Vértes PE, et al. Adolescent Tuning of Association Cortex in Human Structural Brain Networks. Cerebral Cortex (New York, NY : 1991). 2018;28(1):281–94.
32.
Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359(6376):693–7.PubMedPubMedCentralCrossRef
33.
Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47(W1):W191–8.PubMedPubMedCentralCrossRef
34.
Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25(8):1091–3.PubMedPubMedCentralCrossRef
35.
36.
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523.PubMedPubMedCentralCrossRef
37.
Dougherty JD, Schmidt EF, Nakajima M, Heintz N. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 2010;38(13):4218–30.PubMedPubMedCentralCrossRef
38.
Schaefer A, Kong R, Gordon EM, Laumann TO, Zuo XN, Holmes AJ, et al. Local-Global parcellation of the human cerebral cortex from intrinsic functional connectivity MRI. Cerebral Cortex (New York, NY : 1991). 2018;28(9):3095–114.
39.
González-Acosta CA, Escobar MI, Casanova MF, Pimienta HJ, Buriticá E. Von economo neurons in the human medial frontopolar cortex. Front Neuroanat. 2018;12:64.PubMedPubMedCentralCrossRef
40.
Alexander-Bloch AF, Reiss PT, Rapoport J, McAdams H, Giedd JN, Bullmore ET, et al. Abnormal cortical growth in schizophrenia targets normative modules of synchronized development. Biol Psychiatry. 2014;76(6):438–46.PubMedPubMedCentralCrossRef
41.
42.
Shaw GA, Dupree JL, Neigh GN. Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise. Genes Brain Behav. 2020;19(3): e12626.PubMedCrossRef
43.
Schneider N, Greenstreet E, Deoni SCL. Connecting inside out: Development of the social brain in infants and toddlers with a focus on myelination as a marker of brain maturation. Child Dev. 2022;93(2):359–71.PubMedCrossRef
44.
Bassi ZI, Audusseau M, Riparbelli MG, Callaini G, D’Avino PP. Citron kinase controls a molecular network required for midbody formation in cytokinesis. Proc Natl Acad Sci U S A. 2013;110(24):9782–7.PubMedPubMedCentralCrossRef
45.
Nicodemus KK, Callicott JH, Higier RG, Luna A, Nixon DC, Lipska BK, et al. Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging. Hum Genet. 2010;127(4):441–52.PubMedCrossRef
46.
Bludau S, Muhleisen TW, Eickhoff SB, Hawrylycz MJ, Cichon S, Amunts K. Integration of transcriptomic and cytoarchitectonic data implicates a role for MAOA and TAC1 in the limbic-cortical network. Brain Struct Funct. 2018;223(5):2335–42.PubMedPubMedCentralCrossRef
47.
Pennefather JN, Lecci A, Candenas ML, Patak E, Pinto FM, Maggi CA. Tachykinins and tachykinin receptors: a growing family. Life Sci. 2004;74(12):1445–63.PubMedCrossRef
48.
Gouvea ES, Santos AFF, Ota VK, Mrad V, Gadelha A, Bressan RA, et al. The role of the CNR1 gene in schizophrenia: a systematic review including unpublished data. Braz J Psychiatry. 2017;39(2):160–71.PubMedPubMedCentralCrossRef
49.
Sacchetti E, Magri C, Minelli A, Valsecchi P, Traversa M, Calza S, et al. The GRM7 gene, early response to risperidone, and schizophrenia: a genome-wide association study and a confirmatory pharmacogenetic analysis. Pharmacogenomics J. 2017;17(2):146–54.PubMedCrossRef
50.
O’Connell KS, McGregor NW, Lochner C, Emsley R, Warnich L. The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder. Mol Cell Neurosci. 2018;88:300–7.PubMedCrossRef
51.
Cross-Disorder Group of the Psychiatric Genomics C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381(9875):1371–9.CrossRef
52.
Sung KY, Zhang B, Wang HE, Bai YM, Tsai SJ, Su TP, et al. Schizophrenia and risk of new-onset inflammatory bowel disease: a nationwide longitudinal study. Aliment Pharmacol Ther. 2022;55(9):1192–201.PubMedCrossRef
53.
Uellendahl-Werth F, Maj C, Borisov O, Juzenas S, Wacker EM, Jorgensen IF, et al. Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease. Commun Biol. 2022;5(1):80.PubMedPubMedCentralCrossRef
54.
Srivastava AK, Wang Y, Huang R, Skinner C, Thompson T, Pollard L, et al. Human genome meeting 2016: Houston, TX, USA. 28 February - 2 March 2016. Hum Genomics. 2016;10(Suppl 1):12.PubMedPubMedCentralCrossRef
55.
Fruchter E, Goldberg S, Fenchel D, Grotto I, Ginat K, Weiser M. The impact of Herpes simplex virus type 1 on cognitive impairments in young, healthy individuals - a historical prospective study. Schizophr Res. 2015;168(1–2):292–6.PubMedCrossRef
56.
57.
Funk AJ, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH. Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia. Neuropsychopharmacology. 2012;37(4):896–905.PubMedCrossRef
58.
Chuhma N, Mingote S, Kalmbach A, Yetnikoff L, Rayport S. Heterogeneity in Dopamine neuron synaptic actions across the striatum and its relevance for schizophrenia. Biol Psychiatry. 2017;81(1):43–51.PubMedCrossRef
59.
Writing Committee for the Attention-Deficit/Hyperactivity D, Autism Spectrum D, Bipolar D, Major Depressive D, Obsessive-Compulsive D, and Schizophrenia EWG, et al. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. JAMA Psychiatry. 2021;78(1):47–63.CrossRef
60.
Ruzicka WB, Mohammadi S, Davila-Velderrain J, Subburaju S, Tso DR, Hourihan M, et al. Single-cell dissection of schizophrenia reveals neurodevelopmental-synaptic link and transcriptional resilience associated cellular state. Biol Psychiatry. 2021;89(9):S106.CrossRef
61.
Pocklington AJ, Rees E, Walters JT, Han J, Kavanagh DH, Chambert KD, et al. Novel findings from CNVs implicate inhibitory and excitatory signaling complexes in schizophrenia. Neuron. 2015;86(5):1203–14.PubMedPubMedCentralCrossRef
62.
Metadata
Title
Cortical structural changes of morphometric similarity network in early-onset schizophrenia correlate with specific transcriptional expression patterns
Authors
Guanqun Yao
Ting Zou
Jing Luo
Shuang Hu
Langxiong Yang
Jing Li
Xinrong Li
Yuqi Zhang
Kun Feng
Yong Xu
Pozi Liu
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2023
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-023-03201-1

Other articles of this Issue 1/2023

BMC Medicine 1/2023 Go to the issue

Research article

Coding long COVID: characterizing a new disease through an ICD-10 lens

Research article

Cost-effectiveness of the screen-and-treat strategies using HPV test linked to thermal ablation for cervical cancer prevention in China: a modeling study

Research article

Pyrotinib in combination with letrozole for hormone receptor-positive, human epidermal growth factor receptor 2-positive metastatic breast cancer (PLEHERM): a multicenter, single-arm, phase II trial

Research article

Increasing emergency number utilisation is not driven by low-acuity calls: an observational study of 1.5 million emergency calls (2018–2021) from Berlin

Research article

Predicting mortality in acutely hospitalised older patients: the impact of model dimensionality

Research article

Cost-effectiveness of prehabilitation prior to elective surgery: a systematic review of economic evaluations