| Title: | Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders |
| Journal: | JAMA Psychiatry |
| Published: | 1 May 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35353173/ |
| DOI: | https://doi.org/10.1001/jamapsychiatry.2022.0407 |
| URL: | https://jamanetwork.com/journals/jamapsychiatry/articlepdf/2790722/jamapsychiatry_williams_2022_oi_220012_1651602212.45364.pdf |
| Citations: | 125 (102 in last 2 years) as of 8 Aug 2024 |
Publication 12386
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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.</p>
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.</p>
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.</p>
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.</p>
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.</p>
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.</p>
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.</p>
17 Keywords
- Adult
- Autism Spectrum Disorder
- Brain
- Brain-Derived Neurotrophic Factor
- C-Reactive Protein
- Female
- Genome-Wide Association Study
- Humans
- Inflammation
- Interleukin-1
- Interleukin-2
- Interleukin-6
- Magnetic Resonance Imaging
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Schizophrenia
30 Authors
- John A. Williams
- Stephen Burgess
- John Suckling
- Paris Alexandros Lalousis
- Fatima Batool
- Sian Lowri Griffiths
- Edward Palmer
- Andreas Karwath
- Andrey Barsky
- Georgios V. Gkoutos
- Stephen Wood
- Nicholas M. Barnes
- Anthony S. David
- Gary Donohoe
- Joanna C. Neill
- Bill Deakin
- Golam M. Khandaker
- Rachel Upthegrove
- Jack C Rogers
- Valeria Mondelli
- Paola Dazzan
- Carmine Pariante
- James MacCabe
- Alice Egerton
- Peter Jones
- Ed Bullmore
- Nikos Koutsouleris
- Eva Meisenzahl
- David Cotter
- Neil Harrison
1 Application
| Application ID | Title |
|---|---|
| 26999 | Inflammation, depression and cardiovascular disease: examining causal associations |
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