
School of Medicine Publications and Presentations
Document Type
Article
Publication Date
1-2025
Abstract
Phenotypic and genetic relationships between white matter microstructure (i.e., fractional anisotropy [FA]) and peripheral inflammatory responses (i.e., circulating cytokines) have important implications for health and disease. However, it is unclear whether previously discovered genetic correlations between the two traits are due to tissue‐specific white matter architecture or increased free water in the extracellular space. We applied a two‐compartment model to diffusion tensor imaging (DTI) data and estimated tissue‐specific white matter microstructure (FAT) and free water volume (FW). We then quantified their heritability and their genetic correlations with two peripherally circulating proinflammatory cytokines (IL‐8 and TNFα), and compared these correlations to those obtained using traditional FA measures from one‐compartment DTI models. All DTI and cytokine measures were significantly moderately heritable. We confirmed phenotypic and genetic correlations between circulating cytokine levels and single‐compartment FA across the brain (IL‐8: ρ p = −0.16, FDRp = 4.8 × 10−07; ρ g = −0.37 (0.12), FDRp = 0.01; TNFα: ρ p = −0.15, FDRp = 2.4 × 10−07; ρ g = −0.34 (0.12), p = 0.01). However, this relationship no longer reached significance when FA measures were derived using the two‐compartment DTI model (IL‐8: ρ p = −0.04, FDRp = 0.17; ρ g = −0.14 (0.13), FDRp = 0.29; TNFα: ρ p = −0.05, FDRp = 0.10; ρ g = −0.22 (0.13), FDRp = 0.10). There were significant phenotypic and genetic correlations between FW and both IL‐8 (ρ p = 0.19, FDRp = 2.1 × 10−10; ρ g = 0.34 (0.11), FDRp = 0.01) and TNFα (ρ p = 0.16, FDRp = 1.89 × 10−07; ρ g = 0.30 (0.12), FDRp = 0.02). These results have important implications for understanding the mechanisms linking the two phenomena, but they also serve as a cautionary note for those examining associations between white matter integrity using single‐compartment models and inflammatory processes.
Recommended Citation
Rodrigue, A. L., Knowles, E. E. M., Mollon, J., Mathias, S. R., Peralta, J. M., Leandro, A. C., Fox, P. T., Kochunov, P., Olvera, R. L., Almasy, L., Curran, J. E., Blangero, J., & Glahn, D. C. (2025). Genetic Associations Among Inflammation, White Matter Architecture, and Extracellular Free Water. Human brain mapping, 46(1), e70101. https://doi.org/10.1002/hbm.70101
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Publication Title
Human Brain Mapping
DOI
https://doi.org/10.1002/hbm.70101
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
© 2025 The Author(s). Human Brain Mappingpublished by Wiley Periodicals LLC.
This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.