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<p>Genetic variants associated with major depressive disorder (MDD) are enriched in the regulatory genome. Here, we investigate gene-regulatory mechanisms underlying MDD compared to neurotypical controls by combining single-cell chromatin accessibility with gene expression in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals. MDD-associated alterations in chromatin accessibility were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of NR4A2, an activity-dependent TF reactive to stress. The same neurons were enriched for MDD-associated genetic variants, disrupting TF binding sites linked to genes that likely affect synaptic communication. Furthermore, a gray matter microglia cluster exhibited decreased accessibility in individuals with MDD at binding sites bound by TFs known to regulate immune homeostasis. Finally, we identified gene-regulatory effects of MDD-risk variants using sequence-based accessibility predictions, donor-specific genotypes and cell-based assays. These findings shed light on the cell types and regulatory mechanisms through which genetic variation may increase the risk of MDD.</p>

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Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression

  • 期刊论文

  • 发表日期：

    2025年8月5日

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  • Anjali Chawla,
  • Doruk Cakmakci,
  • Laura M. Fiori,
  • Wenmin Zang,
  • Malosree Maitra,
  • Jennie Yang,
  • Dariusz Żurawek,
  • Gabriella Frosi,
  • Reza Rahimian,
  • Haruka Mitsuhashi,
  • Maria Antonietta Davoli,
  • Ryan Denniston,
  • Gary Gang Chen,
  • Volodymyr Yerko,
  • Deborah Mash,
  • Kiran Girdhar,
  • Schahram Akbarian,
  • Naguib Mechawar,
  • Matthew Suderman,
  • Yue Li,
  • Corina Nagy,
  • Gustavo Turecki

摘要

Genetic variants associated with major depressive disorder (MDD) are enriched in the regulatory genome. Here, we investigate gene-regulatory mechanisms underlying MDD compared to neurotypical controls by combining single-cell chromatin accessibility with gene expression in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals. MDD-associated alterations in chromatin accessibility were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of NR4A2, an activity-dependent TF reactive to stress. The same neurons were enriched for MDD-associated genetic variants, disrupting TF binding sites linked to genes that likely affect synaptic communication. Furthermore, a gray matter microglia cluster exhibited decreased accessibility in individuals with MDD at binding sites bound by TFs known to regulate immune homeostasis. Finally, we identified gene-regulatory effects of MDD-risk variants using sequence-based accessibility predictions, donor-specific genotypes and cell-based assays. These findings shed light on the cell types and regulatory mechanisms through which genetic variation may increase the risk of MDD.