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dc.contributor.authorWilliams, John A
dc.contributor.authorBurgess, Stephen
dc.contributor.authorSuckling, John
dc.contributor.authorLalousis, Paris Alexandros
dc.contributor.authorBatool, Fatima
dc.contributor.authorGriffiths, Sian Lowri
dc.contributor.authorPalmer, Edward
dc.contributor.authorKarwath, Andreas
dc.contributor.authorBarsky, Andrey
dc.contributor.authorGkoutos, Georgios V
dc.contributor.authorWood, Stephen
dc.contributor.authorBarnes, Nicholas M
dc.contributor.authorDavid, Anthony S
dc.contributor.authorDonohoe, Gary
dc.contributor.authorNeill, Joanna C
dc.contributor.authorDeakin, Bill
dc.contributor.authorKhandaker, Golam M
dc.contributor.authorUpthegrove, Rachel
dc.contributor.authorPIMS Collaboration
dc.date.accessioned2022-04-29T23:30:52Z
dc.date.available2022-04-29T23:30:52Z
dc.date.issued2022-05-01
dc.identifier.issn2168-622X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336637
dc.description.abstractImportance: Previous in vitro and postmortem research suggests that inflammation may lead to structural brain changes via activation of microglia and/or astrocytic dysfunction in a range of neuropsychiatric disorders. Objective: To investigate the relationship between inflammation and changes in brain structures in vivo and to explore a transcriptome-driven functional basis with relevance to mental illness. Design, Setting, and Participants: This study used multistage linked analyses, including mendelian randomization (MR), gene expression correlation, and connectivity analyses. A total of 20 688 participants in the UK Biobank, which includes clinical, genomic, and neuroimaging data, and 6 postmortem brains from neurotypical individuals in the Allen Human Brain Atlas (AHBA), including RNA microarray data. Data were extracted in February 2021 and analyzed between March and October 2021. Exposures: Genetic variants regulating levels and activity of circulating interleukin 1 (IL-1), IL-2, IL-6, C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were used as exposures in MR analyses. Main Outcomes and Measures: Brain imaging measures, including gray matter volume (GMV) and cortical thickness (CT), were used as outcomes. Associations were considered significant at a multiple testing-corrected threshold of P < 1.1 × 10-4. Differential gene expression in AHBA data was modeled in brain regions mapped to areas significant in MR analyses; genes were tested for biological and disease overrepresentation in annotation databases and for connectivity in protein-protein interaction networks. Results: Of 20 688 participants in the UK Biobank sample, 10 828 (52.3%) were female, and the mean (SD) age was 55.5 (7.5) years. In the UK Biobank sample, genetically predicted levels of IL-6 were associated with GMV in the middle temporal cortex (z score, 5.76; P = 8.39 × 10-9), inferior temporal (z score, 3.38; P = 7.20 × 10-5), fusiform (z score, 4.70; P = 2.60 × 10-7), and frontal (z score, -3.59; P = 3.30 × 10-5) cortex together with CT in the superior frontal region (z score, -5.11; P = 3.22 × 10-7). No significant associations were found for IL-1, IL-2, CRP, or BDNF after correction for multiple comparison. In the AHBA sample, 5 of 6 participants (83%) were male, and the mean (SD) age was 42.5 (13.4) years. Brain-wide coexpression analysis showed a highly interconnected network of genes preferentially expressed in the middle temporal gyrus (MTG), which further formed a highly connected protein-protein interaction network with IL-6 (enrichment test of expected vs observed network given the prevalence and degree of interactions in the STRING database: 43 nodes/30 edges observed vs 8 edges expected; mean node degree, 1.4; genome-wide significance, P = 4.54 × 10-9). MTG differentially expressed genes that were functionally enriched for biological processes in schizophrenia, autism spectrum disorder, and epilepsy. Conclusions and Relevance: In this study, genetically determined IL-6 was associated with brain structure and potentially affects areas implicated in developmental neuropsychiatric disorders, including schizophrenia and autism.
dc.format.mediumPrint-Electronic
dc.publisherAmerican Medical Association (AMA)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectPIMS Collaboration
dc.titleInflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders: A Mendelian Randomization Study.
dc.typeArticle
dc.publisher.departmentMrc Biostatistics Unit
dc.date.updated2022-04-29T11:30:50Z
prism.issueIdentifier5
prism.publicationDate2022
prism.publicationNameJAMA Psychiatry
prism.volume79
dc.identifier.doi10.17863/CAM.84058
dcterms.dateAccepted2022-02-09
rioxxterms.versionofrecord10.1001/jamapsychiatry.2022.0407
rioxxterms.versionVoR
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
dc.identifier.eissn2168-6238
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (204623/Z/16/Z)
pubs.funder-project-idMedical Research Council (MR/S037675/1)
cam.issuedOnline2022-03-30
cam.depositDate2022-04-29
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International