Dynamic neuro-immune regulation of psychiatric risk loci in human neurons
11 affiliations
- 1Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- 2Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- 3Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- 4Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT, USA
- 5Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- 6Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- 7Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT, USA. [email protected]
- 8Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]
- 9Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT, USA. [email protected]
- 10Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT, USA. [email protected]
- 11Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]
Abstract
The immune environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalog genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory cues. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 152 loci from genome-wide association studies (GWAS) of ten brain traits/disorders, empirically dissecting the impact of interleukin-6 (IL-6) and interferon-alpha (IFNα) on transcriptional activity. In human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons, 1,156 active candidate regulatory risk sequences (MPRA-active CRSs) are resolved, including 267 with variant-specific effects (MPRA-emVars) and 61 with variant-by-cytokine interaction effects (interaction MPRA-emVars). Broadly, neuronal immune-mediated regulatory activity is associated with differences in transcription factor binding and chromatin accessibility, the gene targets of which show pleiotropic enrichments for brain, metabolic, and immune disorders. Dynamic genetic regulation mediates neuroimmune effects, informing our understanding of the genomics of psychiatric and neurological traits, mechanisms governing pleiotropy across disorders, and how immune mechanisms mediate genetic risk.
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BibTeX
@article{townsley2026dynamic,
title = {{Dynamic neuro-immune regulation of psychiatric risk loci in human neurons}},
author = {Kayla G. Townsley and S. H. Lee and Sarah Williams and Sam Cartwright and Sophie Cohen and Annabel Sen and Meng Jia and Hannah E. Young and Lee Dobbyn and Michael Deans and Meilín Fernández García and Laura M. Huckins and Kristen Brennand},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-77114-x},
url = {https://doi.org/10.1038/s41467-026-77114-x},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Dynamic neuro-immune regulation of psychiatric risk loci in human neurons
AU - Kayla G. Townsley
AU - S. H. Lee
AU - Sarah Williams
AU - Sam Cartwright
AU - Sophie Cohen
AU - Annabel Sen
AU - Meng Jia
AU - Hannah E. Young
AU - Lee Dobbyn
AU - Michael Deans
AU - Meilín Fernández García
AU - Laura M. Huckins
AU - Kristen Brennand
PY - 2026
DA - 2026/08/27
JO - Nature Communications
DO - 10.1038/s41467-026-77114-x
UR - https://doi.org/10.1038/s41467-026-77114-x
AB - The immune environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalog genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory cues. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 152 loci from genome-wide association studies (GWAS) of ten brain traits/disorders, empirically dissecting the impact of interleukin-6 (IL-6) and interferon-alpha (IFNα) on transcriptional activity. In human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons, 1,156 active candidate regulatory risk sequences (MPRA-active CRSs) are resolved, including 267 with variant-specific effects (MPRA-emVars) and 61 with variant-by-cytokine interaction effects (interaction MPRA-emVars). Broadly, neuronal immune-mediated regulatory activity is associated with differences in transcription factor binding and chromatin accessibility, the gene targets of which show pleiotropic enrichments for brain, metabolic, and immune disorders. Dynamic genetic regulation mediates neuroimmune effects, informing our understanding of the genomics of psychiatric and neurological traits, mechanisms governing pleiotropy across disorders, and how immune mechanisms mediate genetic risk.
SN - 2041-1723
ER -