Summary: Genetic markers linked to inflammation—particularly interleukin-6 (IL-6)—are associated with reduced gray matter in brain regions that are implicated in several neurodevelopmental psychiatric disorders. These results offer fresh insight into biological mechanisms that may contribute to conditions such as schizophrenia and autism spectrum disorder (ASD).
Source: University of Birmingham
Researchers at the University of Birmingham have identified a potential connection between inflammatory genes and the structure of specific brain regions.
Published in JAMA Psychiatry, the study focuses on how inflammation-related genetic variation—most notably involving IL-6—relates to differences in gray matter volume across brain areas previously linked to psychiatric and neurodevelopmental disorders.
The authors propose that targeting inflammatory pathways could provide a new pharmacological approach for disorders where treatment options have not substantially advanced since the mid-20th century introduction of antipsychotics.
The analysis was led by teams from the University of Birmingham’s Institute for Mental Health and Institute of Cancer and Genomic Sciences, with collaborators from the universities of Cambridge, Manchester and Bristol.
Using large-scale data from the UK Biobank, the researchers examined how genetic variants that influence circulating levels of IL-6 and other inflammatory markers correlate with brain imaging measures in more than 20,000 participants.
Their results show particularly strong links between genetically predicted IL-6 levels and lower gray matter volume in temporal and frontal cortical regions. Further transcriptomic analysis using the Allen Human Brain Atlas indicated that genes highly expressed in these regions are enriched for pathways and conditions such as epilepsy, cognitive impairment, and schizophrenia.
Professor Rachel Upthegrove, senior author from the Institute for Mental Health, commented that the findings point to IL-6 as a molecular influence on brain structure in regions relevant to neuropsychiatric illness.
She said: “Our results show that genetic variation linked to systemic inflammation via IL-6 also corresponds with structural differences in brain regions implicated in these disorders. This provides a promising direction for exploring treatments that target IL-6, representing a potential new therapeutic avenue for severe mental illnesses including schizophrenia.”
Dr. John Williams, a lead author from the Institute of Cancer and Genomic Sciences, noted that most current psychiatric medications act on dopamine systems and can be ineffective for many patients or carry substantial side effects.
“Because anti-inflammatory drugs already exist and new compounds can be screened, identifying IL-6 and related inflammatory pathways as linked to brain structure creates an important new route to investigate treatments,” he said.
This study is part of the PIMS (Psychosis Immune Mechanism Stratified Medicine) program, coordinated by the University of Birmingham to study the interplay between immune signaling and psychosis. Planned next steps include experimental work to inhibit IL-6 and replication of the UK Biobank findings in more diverse cohorts.
About this genetics, inflammation, and psychiatry research news
Author: Press Office
Source: University of Birmingham
Contact: Press Office – University of Birmingham
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Original Research: Open access. “Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders – A Mendelian Randomization Study” by Rachel Upthegrove et al., JAMA Psychiatry
Abstract
Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders – A Mendelian Randomization Study
Importance
Prior laboratory and postmortem studies suggest that inflammatory processes—through microglial activation or astrocyte dysfunction—can contribute to structural brain changes observed across several neuropsychiatric conditions. This study seeks to test those relationships in living human data.
Objective
To evaluate whether genetic proxies for inflammatory markers are associated with in vivo measures of brain structure, and to explore transcriptomic patterns that could explain links to psychiatric illness.
Design, Setting, and Participants
The research used a multistage analytic strategy combining Mendelian randomization (MR), gene expression correlation, and network connectivity analyses. The primary sample comprised 20,688 UK Biobank participants with clinical, genomic, and neuroimaging data. Separately, RNA microarray data from six neurotypical postmortem brains in the Allen Human Brain Atlas were analyzed. Data extraction occurred in February 2021, with analyses performed between March and October 2021.
Exposures
Genetic variants that regulate circulating levels or activity of interleukins (IL-1, IL-2, IL-6), C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) served as instrumental exposures in MR analyses.
Main Outcomes and Measures
Primary outcomes were brain imaging measures, including regional gray matter volume (GMV) and cortical thickness (CT). Statistical significance was evaluated using a multiple testing–corrected threshold of P < 1.1 × 10−4. For transcriptomic follow-up, regions identified in MR were mapped to the Allen Human Brain Atlas, and differentially expressed genes were tested for biological and disease enrichment as well as protein-protein interaction connectivity.
Results
Among the 20,688 UK Biobank participants (52.3% female; mean age 55.5 years), genetically predicted IL-6 levels were significantly associated with GMV reductions in the middle temporal gyrus (z = 5.76; P = 8.39 × 10−9), inferior temporal cortex (z = 3.38; P = 7.20 × 10−5), fusiform gyrus (z = 4.70; P = 2.60 × 10−7), and frontal cortex (z = −3.59; P = 3.30 × 10−5). Cortical thickness in the superior frontal region was also associated (z = −5.11; P = 3.22 × 10−7).
No associations reached corrected significance for IL-1, IL-2, CRP, or BDNF. In the Allen Human Brain Atlas sample (five of six donors male; mean age 42.5 years), coexpression analysis revealed a tightly interconnected network of genes preferentially expressed in the middle temporal gyrus (MTG). This MTG network formed a significantly connected protein-protein interaction module with IL-6 and showed enrichment for biological processes and disease pathways implicated in schizophrenia, autism spectrum disorder, and epilepsy.
Conclusions and Relevance
This study finds that genetically determined IL-6 levels are associated with structural brain differences in regions tied to developmental neuropsychiatric disorders. These results support further investigation of IL-6–related inflammatory mechanisms as potential contributors to conditions such as schizophrenia and autism, and as candidate targets for future therapeutic strategies.