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Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Seidlitz, Jakob 
Whitaker, Kirstie J  ORCID logo  https://orcid.org/0000-0001-8498-4059
Romero-Garcia, Rafael 
Clifton, Nicholas E 

Abstract

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.

Description

Keywords

Allen Human Brain Atlas, dysconnectivity, morphometric similarity, network neuroscience, psychosis, Adult, Brain, Case-Control Studies, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Nerve Net, Neural Pathways, Neuroimaging, Psychotic Disorders, Schizophrenia

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

116

Publisher

Proceedings of the National Academy of Sciences

Rights

All rights reserved
Sponsorship
European Commission (603196)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Alan Turing Institute (AT/120001/005)
MQ: Transforming Mental Health (MQ17-24 Vertes)
Medical Research Council (MR/K020706/1)
This study was supported by grants from the European Commission (PSYSCAN - Translating neuroimaging findings from research into clinical practice; ID: 603196) and the NIHR Cambridge Biomedical Research Centre (Mental Health). SEM holds a Henslow Fellowship at Lucy Cavendish College, University of Cambridge, funded by the Cambridge Philosophical Society. PEV was supported by the Medical Research Council (MR/K020706/1) and an MQ fellowship (MQF17_24) and is a Fellow of the Alan Turing Institute funded under the EPSRC grant EP/N510129/1. KJW was funded by an Alan Turing Institute Research Fellowship under EPSRC Research grant TU/A/000017. ETB is supported by a NIHR Senior Investigator Award.