Immune markers mediate genetic relationships between immune diseases and psychiatric disorders
7 affiliations
- 1Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado, United States of America
- 2Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America
- 3Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- 4Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America
- 5Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
- 6Massachusetts General Hospital Brigham, Boston, Massachusetts, United States of America
- 7Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract
This study explored the genetic links between 11 immune-mediated diseases and 13 psychiatric disorders, addressing the limited understanding of the underlying biological mechanisms linking these illnesses. Utilizing genomic structural equation modeling, we investigated whether the genetic liability for 14 immune markers (e.g., C-reactive protein [CRP], interleukin-6 [IL-6]) mediated associations between latent genomic factors of immune-mediated diseases (e.g., autoimmune) and psychiatric disorders (e.g., internalizing). While the literature extensively describes the psychiatric relevance of CRP, results indicated this is better explained by its biological precursor, IL-6. This is evidenced by highly attenuated associations of psychiatric traits with CRP when accounting for overlapping signal of IL6. Overall, the genetic liability of six immune markers significantly mediated 11 psychiatric-immune disease genetic relationships. For example, IL-6 mediated 60% of the genetic link between an internalizing factor and Crohn’s disease. Identified markers often evinced mediating effects for multiple disorder clusters and many immune-psychiatric relationships were mediated by multiple markers. At the same time, highlighting their diagnostic relevance, only a subset of examined immune markers were significant mediators. These findings provide mechanistic insight by pinpointing the immune markers that may be most critical to the psychiatric-immune disease link, which notably did not include CRP. Author summary: In this study, we investigated the long-observed link between immune-mediated diseases, such as Crohn’s disease or lupus, and psychiatric disorders like depression and anxiety. While the connection between the immune system and mental health is well-documented, the specific biological pathways that connect these two areas remain unclear. To address this, we used large-scale genetic data to examine whether the genetic liability for specific immune markers—proteins that signal activity in the immune system—act as mediators in these relationships. Our findings revealed that only a specific subset of immune markers, most notably Interleukin-6 (IL-6), significantly explained the genetic overlap between these conditions. Interestingly, while C-reactive protein (CRP) is frequently cited in medical literature as a key biomarker for psychiatric risk, our analysis showed that its influence is likely a byproduct of its relationship with IL-6. When we accounted for IL-6, the independent effect of CRP largely disappeared. These results help refine our understanding of the biological mechanisms driving the co-occurrence of immune and psychiatric illnesses. By identifying the most relevant markers, we hope to guide future research toward more precise diagnostic tools and targeted treatments.
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BibTeX
@article{breunig2026immune,
title = {{Immune markers mediate genetic relationships between immune diseases and psychiatric disorders}},
author = {Sophie Breunig and Kristen M. Kelly and Lukas S. Schaffer and Jeremy M. Lawrence and Younga Heather Lee and Elizabeth W. Karlson and Andrew D. Grotzinger},
journal = {PLOS Genetics},
year = {2026},
month = sep,
doi = {10.1371/journal.pgen.1012328},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012328},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune markers mediate genetic relationships between immune diseases and psychiatric disorders
AU - Sophie Breunig
AU - Kristen M. Kelly
AU - Lukas S. Schaffer
AU - Jeremy M. Lawrence
AU - Younga Heather Lee
AU - Elizabeth W. Karlson
AU - Andrew D. Grotzinger
PY - 2026
DA - 2026/09/30
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012328
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012328
AB - This study explored the genetic links between 11 immune-mediated diseases and 13 psychiatric disorders, addressing the limited understanding of the underlying biological mechanisms linking these illnesses. Utilizing genomic structural equation modeling, we investigated whether the genetic liability for 14 immune markers (e.g., C-reactive protein [CRP], interleukin-6 [IL-6]) mediated associations between latent genomic factors of immune-mediated diseases (e.g., autoimmune) and psychiatric disorders (e.g., internalizing). While the literature extensively describes the psychiatric relevance of CRP, results indicated this is better explained by its biological precursor, IL-6. This is evidenced by highly attenuated associations of psychiatric traits with CRP when accounting for overlapping signal of IL6. Overall, the genetic liability of six immune markers significantly mediated 11 psychiatric-immune disease genetic relationships. For example, IL-6 mediated 60% of the genetic link between an internalizing factor and Crohn’s disease. Identified markers often evinced mediating effects for multiple disorder clusters and many immune-psychiatric relationships were mediated by multiple markers. At the same time, highlighting their diagnostic relevance, only a subset of examined immune markers were significant mediators. These findings provide mechanistic insight by pinpointing the immune markers that may be most critical to the psychiatric-immune disease link, which notably did not include CRP. Author summary: In this study, we investigated the long-observed link between immune-mediated diseases, such as Crohn’s disease or lupus, and psychiatric disorders like depression and anxiety. While the connection between the immune system and mental health is well-documented, the specific biological pathways that connect these two areas remain unclear. To address this, we used large-scale genetic data to examine whether the genetic liability for specific immune markers—proteins that signal activity in the immune system—act as mediators in these relationships. Our findings revealed that only a specific subset of immune markers, most notably Interleukin-6 (IL-6), significantly explained the genetic overlap between these conditions. Interestingly, while C-reactive protein (CRP) is frequently cited in medical literature as a key biomarker for psychiatric risk, our analysis showed that its influence is likely a byproduct of its relationship with IL-6. When we accounted for IL-6, the independent effect of CRP largely disappeared. These results help refine our understanding of the biological mechanisms driving the co-occurrence of immune and psychiatric illnesses. By identifying the most relevant markers, we hope to guide future research toward more precise diagnostic tools and targeted treatments.
SN - 1553-7404
ER -