Immune Signals in the Blood May Explain Why Body and Mind Share Genetic Risk

For decades, clinicians have noticed that patients with autoimmune and inflammatory diseases seem to experience depression, anxiety, psychosis, and other psychiatric conditions at rates far higher than the general population. What has remained stubbornly unclear is whether that overlap is coincidence, consequence, or something written into the genome itself. A new study published in PLOS Genetics by Sophie Breunig, Andrew Grotzinger, and colleagues now offers one of the most detailed genetic maps to date of how these two domains of illness are connected, and it points to specific, measurable molecules in the blood as the likely couriers of that shared risk. Rather than treating the immune system as a vague background influence on mental health, the researchers identified which of fourteen circulating immune markers actually carry the genetic signal between eleven immune-mediated diseases and thirteen psychiatric disorders.

The team’s central tool was genomic structural equation modeling, a statistical framework that allows researchers to work with latent factors, meaning unobserved variables that summarize the genetic overlap among groups of related conditions. Instead of asking whether, say, rheumatoid arthritis is genetically correlated with depression in isolation, the investigators first organized the immune-mediated diseases into latent factors such as an overall autoimmune liability, and organized psychiatric disorders into latent factors such as an internalizing dimension that captures shared genetic risk across depression, anxiety, and related conditions. This approach mirrors how clinical reality actually presents: patients rarely carry a single diagnosis, and genetic risk similarly clusters across diagnostic boundaries. By modeling these clusters, the study could ask a more powerful question than pairwise correlations allow.

That question was whether the genetic liability for specific immune markers, circulating in measurable quantities in the blood, statistically mediates the relationship between the immune disease factors and the psychiatric disorder factors. Mediation, in this context, means that part of the genetic correlation between two clusters of illness flows through a third variable. The fourteen markers examined included some of the most intensively studied molecules in psychoneuroimmunology, among them C-reactive protein, universally measured in clinical settings as a marker of systemic inflammation, and interleukin-6, a signaling molecule of the immune system that stimulates the liver to produce C-reactive protein in the first place. Other markers spanned additional branches of immune signaling, giving the analysis coverage of multiple biological pathways rather than a single inflammatory axis.

The headline finding is a striking correction to a widely repeated narrative. C-reactive protein has been described extensively in the literature as psychiatrically relevant, with elevated levels repeatedly linked to depression and other conditions in large cohort studies. But when the researchers accounted for the overlapping genetic signal with interleukin-6, the associations between psychiatric traits and C-reactive protein were highly attenuated, essentially shrinking toward zero. In other words, the psychiatric relevance long attributed to C-reactive protein appears to be better explained by its biological precursor. Because interleukin-6 sits upstream, driving the production of C-reactive protein, this reframing matters enormously for how researchers interpret inflammation measurements in psychiatry. A blood test result that looks like a C-reactive protein story may in fact be an interleukin-6 story wearing a different label.

Across the full set of analyses, the genetic liability of six immune markers significantly mediated eleven distinct psychiatric-immune disease genetic relationships. The magnitude of some of these mediated effects was remarkable. Interleukin-6 alone mediated roughly sixty percent of the genetic link between the latent internalizing factor and Crohn’s disease, an inflammatory bowel condition. That means a majority of the shared genetic architecture between a cluster of mood and anxiety related disorders and a chronic gut inflammation disease appears to travel through variation in circulating levels of a single immune signaling molecule. For a field that has often spoken in generalities about inflammation and mental health, this is the kind of quantitative specificity that can redirect research programs.

Equally informative was the pattern of the mediation effects. The identified markers did not behave as narrow, one-to-one bridges between a single immune disease and a single psychiatric diagnosis. Instead, many of the significant markers showed mediating effects across multiple disorder clusters, and many individual immune-psychiatric relationships were mediated by more than one marker. This suggests a network-like architecture in which a small set of circulating immune molecules serves as a shared conduit connecting diverse forms of physical and mental illness. At the same time, the study’s diagnostic relevance comes from what it excluded: only a subset of the fourteen examined markers emerged as significant mediators. The immune system produces hundreds of measurable proteins, and this analysis indicates that the psychiatric-immune connection is not diffuse noise across all of them but concentrated in a specific, identifiable handful.

The technical machinery behind these conclusions deserves attention, because genetic mediation studies are easy to get wrong. Genomic structural equation modeling combines genome-wide association study summary statistics, which estimate the genetic contribution to each trait from hundreds of thousands of genetic variants across large populations, into models that can test whether correlations between traits are consistent with an underlying causal pathway. Because the method works with summary statistics rather than individual patient data, it can integrate enormous samples from separate consortia studying immune diseases, psychiatric disorders, and blood biomarkers. The mediation tests then ask whether the genetic correlation between, for example, the autoimmune factor and the internalizing factor diminishes once the genetic variance shared with interleukin-6 levels is statistically accounted for. A substantial reduction indicates that the marker carries a meaningful share of the relationship.

What makes this mechanistic framing biologically plausible is the established physiology of the molecules involved. Interleukin-6 is a cytokine released by immune cells during inflammation, and it crosses into and signals within the central nervous system, where it can influence neurotransmitter metabolism, neural circuit function, and behavior. C-reactive protein, produced by the liver under interleukin-6 stimulation, is generally viewed as a downstream readout of inflammatory activity rather than an active driver. The study’s statistical results align neatly with this biology: the upstream signaling molecule, not the downstream readout, carries the genetic relationship to psychiatric liability. This convergence between statistical mediation and known molecular pathways strengthens the case that the findings reflect genuine biology rather than statistical artifact.

The clinical implications are considerable, though the authors’ findings are genetic and mediational, not proof of causation in individual patients. If a substantial fraction of the genetic overlap between immune diseases and psychiatric disorders flows through a small set of immune markers, then those markers become prime candidates for intervention studies, biomarker development, and patient stratification. A patient with Crohn’s disease and elevated interleukin-6 might represent a distinct subgroup whose psychiatric risk is mechanistically tied to their inflammatory disease, potentially warranting closer monitoring or treatments that target the shared pathway. Conversely, the finding that C-reactive protein is not itself a significant mediator cautions against continuing to treat it as the default inflammatory biomarker in psychiatric research, a practice the authors’ results suggest may have been tracking the wrong molecule.

More broadly, the study exemplifies a shift in how genetics is being used to dissect the architecture of comorbidity. Rather than cataloging correlations and stopping there, methods like genomic structural equation modeling allow researchers to propose and test specific mechanistic hypotheses about how genetic liabilities travel between organ systems. The immune system and the brain have long been studied by separate communities with separate journals, separate conferences, and separate vocabularies. Findings like these, which pinpoint interleukin-6 and five other markers as the molecular bridges linking eleven immune diseases to thirteen psychiatric disorders, provide a common quantitative language for both. The work does not close the book on the immune-psychiatric connection, but it does something arguably more valuable: it tells researchers exactly which pages to read next, and which molecules to watch when the story of body and mind continues to unfold.

Subject of Research: Genetic mediation of relationships between immune-mediated diseases and psychiatric disorders by circulating immune markers

Article Title: Immune markers mediate genetic relationships between immune diseases and psychiatric disorders

Article References: Breunig, S., Kelly, K. M., Schaffer, L. S., Lawrence, J. M., Lee, Y. H., Karlson, E. W., & Grotzinger, A. D. (2026). Immune markers mediate genetic relationships between immune diseases and psychiatric disorders. PLOS Genetics, 22(9), e1012328. https://doi.org/10.1371/journal.pgen.1012328

Image Credits: AI Generated

DOI: 10.1371/journal.pgen.1012328

Keywords: genomic structural equation modeling, interleukin-6, C-reactive protein, immune-mediated diseases, psychiatric disorders, genetic correlation, mediation analysis, Crohn's disease, internalizing disorders, inflammation, GWAS, psychoneuroimmunology