Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation

Systematic characterization of how genetic variation modulates gene regulation in a cell type specific context is essential for understanding complex traits. To address this question, we profiled gene expression and chromatin state of cells from healthy retinae of 20 human donors with a single-cell multiomics approach, and performed genomic sequencing. sc-eQTLs, sc-caQTL, sc-ASCA and sc-ASE were mapped in major retinal cell types. By integrating these results, we identified and characterized regulatory elements and genetic variants effective on gene regulation in individual cell types. Most of the identified sc-eQTLs and sc-caQTLs exhibit cell type-specific effects. Interestingly, the cis-elements harboring genetic variants with cell type-specific effects tend to be accessible in multiple cell types. Lastly, we identified the enriched cell types, fine-mapped candidate causal variants and genes, and uncovered cell type-specific regulatory mechanism underlying GWAS loci.

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