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

Michael Cheng; Melody Mao; Wenjing Meng; Joanna Jacobus; Emily A Troyer; Everett L Delfel; Emily L Dennis; Elisabeth A Wilde; Tracy Abildskov; Nicola L de Souza; Florin Vaida; Jeffrey E Max; Xia Yang

doi:10.1038/s41540-026-00681-8

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

NPJ Syst Biol Appl. 2026 Mar 13. doi: 10.1038/s41540-026-00681-8. Online ahead of print.

Authors

Michael Cheng^{1

2}, Melody Mao¹, Wenjing Meng³, Joanna Jacobus⁴, Emily A Troyer⁴, Everett L Delfel⁵, Emily L Dennis^{6

7}, Elisabeth A Wilde^{6

7}, Tracy Abildskov^{6

7}, Nicola L de Souza⁶, Florin Vaida⁸, Jeffrey E Max⁹, Xia Yang^{10

11

12

13

14

15

16}

Affiliations

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 Division of Biostatistics, School of Public Health, University of California, San Diego, San Diego, CA, USA. fvaida@health.ucsd.edu.
⁹ Department of Psychiatry, University of California, San Diego, San Diego, CA, USA. jmax@health.ucsd.edu.
¹⁰ Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA. xyang123@ucla.edu.
¹¹ Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA. xyang123@ucla.edu.
¹² Molecular, Cellular and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA. xyang123@ucla.edu.
¹³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. xyang123@ucla.edu.
¹⁴ Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. xyang123@ucla.edu.
¹⁵ Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA. xyang123@ucla.edu.
¹⁶ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA. xyang123@ucla.edu.

PMID: 41826372
DOI: 10.1038/s41540-026-00681-8

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.

Abstract

Grants and funding