Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders: A Mendelian Randomization Study.
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Authors
Williams, John A
Suckling, John
Lalousis, Paris Alexandros
Batool, Fatima
Griffiths, Sian Lowri
Palmer, Edward
Karwath, Andreas
Barsky, Andrey
Gkoutos, Georgios V
Wood, Stephen
Barnes, Nicholas M
David, Anthony S
Donohoe, Gary
Neill, Joanna C
Deakin, Bill
Khandaker, Golam M
Upthegrove, Rachel
PIMS Collaboration
Publication Date
2022-05-01Journal Title
JAMA Psychiatry
ISSN
2168-622X
Publisher
American Medical Association (AMA)
Volume
79
Issue
5
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Williams, J. A., Burgess, S., Suckling, J., Lalousis, P. A., Batool, F., Griffiths, S. L., Palmer, E., et al. (2022). Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders: A Mendelian Randomization Study.. JAMA Psychiatry, 79 (5) https://doi.org/10.1001/jamapsychiatry.2022.0407
Abstract
IMPORTANCE: 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.
Keywords
PIMS Collaboration
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MR/S037675/1)
Identifiers
External DOI: https://doi.org/10.1001/jamapsychiatry.2022.0407
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336637
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