Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders: A Mendelian Randomization Study

Key Points

Question
Is there evidence for a potential relationship between inflammation and brain structure, and is this relevant for schizophrenia and other neuropsychiatric disorders?

Findings
In this mendelian randomization study including 20 688 participants in the UK Biobank, genetically predicted levels of interleukin 6 were associated with gray matter volume and cortical thickness primarily in the middle temporal gyrus and superior frontal region. The middle temporal gyrus overexpressed a number of genes relevant to interleukin 6 pathway proteins and neuropsychiatric disorder ontologies, including schizophrenia and autism spectrum disorder.

Meaning
This study found that inflammation may be associated with brain structure and may be an early predeterminant of neuropsychiatric conditions, which has important implications for identification of risk and novel treatments.


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.