Could IL-6 Expression Affect Brain Structure and Contribute to Neuropsychiatric Disorders?

Artificial neural network, illustration.
Data for this study were sourced from the United Kingdom (UK) Biobank and the Allen Human Brain Atlas (AHBA).

Genetically determined interleukin (IL)-6 was associated with brain structure and may affect areas implicated in the development of neuropsychiatric disorders. These findings were published in JAMA Psychiatry.

Data for this study were sourced from the United Kingdom (UK) Biobank and the Allen Human Brain Atlas (AHBA). A Mendelian randomization approach was used to predict IL-1, IL-2, IL-6, C reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) levels. Genetically predicted markers for inflammation were related with gray matter volume and cortical thickness.

Among the 20,688 participants with data in the UK Biobank, 52.3% were women and were aged mean 55.5 (SD, 7.5) years and among the 6 participants with data in the AHBA, 83% were men and were aged mean 42.3 (SD, 13.4) years.

Genetically predicted IL-6 levels were associated with 33 brain imaging measures (P <1.1×10-4). No IL-1, IL-2, CRP, or BDNF predictions were significant after correcting for multiple testing.

The significant regions for IL-6 levels were in the temporo-occipital part of the middle temporal gyrus (P =8.39×10-9) and the posterior division of the temporal fusiform cortex (P =3.22×10-7). The middle temporal gyrus, fusiform gyrus, and superior frontal gyrus had the strongest associations with IL-6.

Using data from differentially expressed genes in the middle temporal gyrus, a protein-protein interaction network with 43 nodes and 30 edges was observed, which was larger than expected (P =4.54×10-9).

Several of the genes in the network interact with IL-6 (neuropeptide Y [NPY], met proto-oncogene [MET], cholecystokinin [CCK], muscular LMNA–interacting protein [MLIP], and heat shock protein family B member 3 [HSPB3]).

In addition, these genes are likely involved with epilepsy (odds ratio [OR], 4.66; 95% CI, 3.17-6.71; P =3.2×10-10), autism spectrum disorder (OR, 3.70; 95% CI, 2.42-5.50; P =1.1×10-5), schizophrenia (OR, 2.44; 95% CI, 1.87-3.16; P =5.7×10-7), psychotic disorder (OR, 2.43; 95% CI, 1.86-3.15; P =6.5×10-7), and cognitive disorder (OR, 2.37; 95% CI, 1.86-2.99; P =2.8×10-8).

This study may have been biased by assuming that gene expression is correlated in brain hemispheres.

The study authors concluded, “This mendelian randomization study found that IL-6 was associated with changes in brain structure, with associations strongest in the middle temporal gyrus where several genes are differentially overexpressed compared with the whole brain. These genes form a highly connected network at the protein level and functionally contribute to diseases and phenotypes related to schizophrenia, autism spectrum disorder, and epilepsy. This suggests a genetically mediated, tissue-specific neuroinflammatory cascade relevant to brain structure in neuropsychiatric disorders.”


Williams JA, Burgess S, Suckling J, et al. Inflammation and brain structure in schizophrenia and other neuropsychiatric disorders: a mendelian randomization study. JAMA Psychiatry. Published online March 30, 2022. doi:10.1001/jamapsychiatry.2022.0407