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Background <p>Intracerebral hemorrhage (ICH) lacks effective neuroprotective therapies. We integrated cell type–resolved genetic inference with single-cell profiling to map putative causal programs and multicellular circuitry relevant to ICH.</p> Methods <p>Cis-eQTLs from eight human brain cell types were used as instruments for two-sample Mendelian randomization (MR), with an ICH meta-analysis from large biobanks and a stroke consortium as the outcome. Instruments were LD-pruned and restricted to strong variants (F &gt; 10). Inverse-variance weighting (IVW) was the primary estimator, supported by robustness methods, heterogeneity/pleiotropy diagnostics, and false discovery rate control. Experimental validation used mouse collagenase ICH single-cell RNA-seq at 24&#xa0;h (<i>n</i> = 3 sham; <i>n</i> = 3 ICH) with Seurat integration, composition testing, Slingshot pseudotime, and CellChat. An independent mouse cohort underwent qRT–PCR for selected genes.</p> Results <p>The ICH meta-analysis showed acceptable genomic control, supporting downstream MR. We identified 524 nominal gene–cell type associations, with a glia-weighted signal landscape. Enrichment implicated autophagy/mitophagy, antigen processing, cytoskeletal and vesicular trafficking, endothelial matrix–adhesion programs, ferroptosis, and myelin stress pathways. In mouse scRNA-seq, disease-associated microglia expanded with reciprocal loss of homeostatic microglia and increased neutrophils and T cells. Prioritized genes showed directional concordance; qRT–PCR confirmed ARPC3 and EIF2AK2 upregulation and TBCK and SPECC1 downregulation in ICH versus sham. Pseudotime supported a shift toward disease-associated microglial states, and CellChat indicated increased network interaction strength with microglia and endothelium as hubs.</p> Conclusions <p>Cell type–specific MR combined with single-cell validation highlights neuroimmune and neurovascular programs in ICH and links genetic signals to state transitions and inferred intercellular communication.</p>

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Cell type resolved MR based on brain single cell eQTLs corroborated by single cell RNA sequencing uncovers neuroimmune and vascular programs in intracerebral hemorrhage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Sha Yang,
  • Xiangqian Ren,
  • Mei Deng,
  • Junchi Luo,
  • Guoqiang Han,
  • Tao Xiong,
  • Tao Luo,
  • Jiqin Zhang,
  • Ying Tan,
  • Yunjia Hu

摘要

Background

Intracerebral hemorrhage (ICH) lacks effective neuroprotective therapies. We integrated cell type–resolved genetic inference with single-cell profiling to map putative causal programs and multicellular circuitry relevant to ICH.

Methods

Cis-eQTLs from eight human brain cell types were used as instruments for two-sample Mendelian randomization (MR), with an ICH meta-analysis from large biobanks and a stroke consortium as the outcome. Instruments were LD-pruned and restricted to strong variants (F > 10). Inverse-variance weighting (IVW) was the primary estimator, supported by robustness methods, heterogeneity/pleiotropy diagnostics, and false discovery rate control. Experimental validation used mouse collagenase ICH single-cell RNA-seq at 24 h (n = 3 sham; n = 3 ICH) with Seurat integration, composition testing, Slingshot pseudotime, and CellChat. An independent mouse cohort underwent qRT–PCR for selected genes.

Results

The ICH meta-analysis showed acceptable genomic control, supporting downstream MR. We identified 524 nominal gene–cell type associations, with a glia-weighted signal landscape. Enrichment implicated autophagy/mitophagy, antigen processing, cytoskeletal and vesicular trafficking, endothelial matrix–adhesion programs, ferroptosis, and myelin stress pathways. In mouse scRNA-seq, disease-associated microglia expanded with reciprocal loss of homeostatic microglia and increased neutrophils and T cells. Prioritized genes showed directional concordance; qRT–PCR confirmed ARPC3 and EIF2AK2 upregulation and TBCK and SPECC1 downregulation in ICH versus sham. Pseudotime supported a shift toward disease-associated microglial states, and CellChat indicated increased network interaction strength with microglia and endothelium as hubs.

Conclusions

Cell type–specific MR combined with single-cell validation highlights neuroimmune and neurovascular programs in ICH and links genetic signals to state transitions and inferred intercellular communication.