Multi-omics and single-cell CRISPRi screening maps Alzheimer's GWAS variants to TSPAN14 effector gene in microglia
By
Alessandra Chesi1 Send email to [email protected]
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Summary
This study presents a variant-to-gene (V2G) mapping effort for Alzheimer disease (AD) that integrates ten brain-relevant genomics datasets—including promoter Capture C, ATAC-seq, and RNA-seq from microglia, neurons, and astrocytes—to fine-map AD GWAS variants and identify effector genes. The researchers performed a single-cell CRISPRi Perturb-seq screen targeting 74 candidate genes, identifying a microglia-specific enhancer regulating TSPAN14, which links genetic risk to inflammatory and adhesion pathways. The work provides a scalable framework for functional interpretation of complex disease loci.
Key quotes
· 5 pulledGenome-wide association studies (GWASs) have uncovered many associations for human complex diseases, but functional dissection of the discovered loci has lagged behind.
We present a variant-to-gene (V2G) mapping effort for Alzheimer disease (AD) leveraging the most recent AD GWAS meta-analyses.
We integrated ten brain-relevant genomics datasets—including promoter Capture C, ATAC-seq, and RNA-seq from microglia, neurons, and astrocytes—to fine-map AD GWAS variants and identify effector genes.
We then performed a single-cell CRISPRi Perturb-seq screen targeting 74 candidate genes.
It identifies a microglia-specific enhancer regulating TSPAN14, linking genetic risk to inflammatory and adhesion pathways and providing a scalable framework for functional interpretation of complex disease loci.
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