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<p>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 <i>APP</i> for synaptic signaling in excitatory neurons, <i>COX5A</i> for mitochondrial function in inhibitory neurons, <i>MOG</i> for myelination in oligodendrocytes in the hippocampus; <i>GRM7</i> for synaptic signaling in excitatory neurons, <i>SV2A</i> for synaptic signaling in inhibitory neurons, and <i>MOG</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • 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

摘要

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.