Neuronal and glial networks interact with traumatic brain injury to modulate cognition in ABCD study.

Overview

1. Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA USA
2. Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA USA
3. Division of Biostatistics, School of Public Health, University of California, San Diego, San Diego, CA USA
4. Department of Psychiatry, University of California, San Diego, San Diego, CA USA
5. Joint Doctoral Program in Clinical Psychology, San Diego State University / University of California, San Diego, San Diego, CA USA
6. Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT USA
7. George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT USA
8. Molecular, Cellular and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA USA
9. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA USA
10. Brain Research Institute, University of California, Los Angeles, Los Angeles, CA USA
11. Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA USA
12. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA

Abstract

Mild traumatic brain injury (mTBI) disproportionately affects children and adolescents and has been associated with poorer neurocognitive performance, but the biological mechanisms driving symptom variability and severity remain understudied. In accordance with the omnigenic disease model, we integrated gene-by-mTBI interaction genome-wide association studies on neurocognition from the Adolescent Brain Cognitive Development (ABCD) cohort with single-cell RNA sequencing gene regulatory networks to elucidate the cell type-specific key regulators and molecular mechanisms governing neurocognitive outcome of mTBI, specifically learning and memory performance. Our analysis revealed distinct network regulators in neuronal and glial cell types across hippocampal and cortical brain regions to orchestrate key neurodevelopmental pathways. Examples include APP for synaptic signaling in excitatory neurons, COX5A for mitochondrial function in inhibitory neurons, MOG for myelination in oligodendrocytes in the hippocampus; GRM7 for synaptic signaling in excitatory neurons, SV2A for synaptic signaling in inhibitory neurons, and MOG for myelination in oligodendrocytes in the cortex. These mechanisms also associate with learning and memory through pathway-based polygenic risk score modeling in ABCD. Our findings provide brain region- and cell type-specific insights into the complex regulatory network landscape of mTBI pathology and potential therapeutic candidates at the pathway and network levels.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• portal.brain-map.org/atlases-and-data/rnaseq, at Allen Brain Map; found in “Data availability”

Data availability

All data pertaining to ABCD is available through the National Institute of Mental Health Data Archive (NDA). The Gene Ontology biological pathways were downloaded from Molecular Signature Databases (https://www.gsea-msigdb.org/gsea/msigdb/human/collections.jsp#C5). The single-cell RNA-seq data were downloaded from Allen Brain Atlas (https://portal.brain-map.org/atlases-and-data/rnaseq). Data analysis scripts can be found in our GitHub repository https://github.com/XiaYangLabOrg/ABCD_GWAS or by contacting the lead author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 3 keywords, 10 MeSH terms, 4 funders, 99 references.

Cite

This paper

Cheng, M., Mao, M., Meng, W., Jacobus, J., Troyer, E. A., Delfel, E. L., Dennis, E. L., Wilde, E. A., Abildskov, T., de Souza, N. L., Vaida, F., Max, J. E., & Yang, X. (2026). Neuronal and glial networks interact with traumatic brain injury to modulate cognition in ABCD study. NPJ systems biology and applications, 12(1), 60. https://doi.org/10.1038/s41540-026-00681-8

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