Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens
Level 5 - mechanism / opinion, no new human data
Laboratory functional genomics study utilizing in vitro pooled CRISPR screens and multi-omics profiling.
OpenAlex W4368347467 · doi:10.1126/science.adh7699
What was done
Ancestrally diverse biobank-scale GWAS data for blood traits were integrated with massively parallel pooled CRISPR screens, single-cell transcriptomic and proteomic sequencing, and precise base-editing variant insertion to identify functional mechanisms at noncoding loci.
What was found
The screen identified 124 cis-target genes across 91 noncoding blood trait GWAS loci. Targeted base editing linked specific genetic variants to changes in gene expression. In cases where cis-target genes encoded transcription factors or microRNAs, trans-effect networks were resolved and demonstrated polygenic enrichment for additional GWAS variants. Specific statistical effect sizes and donor numbers were not reported in the abstract.
Why it matters
It establishes a scalable experimental approach to systematically map noncoding disease- and trait-associated GWAS variants to their direct cis-target genes and broader downstream cellular networks.
Limits
The abstract reports no participant counts, cohort sizes, or quantitative effect sizes. Functional validations were restricted to blood trait loci and in vitro cellular assays, which may not capture full in vivo physiological contexts across different cell types.
Cited by
- supports Single-cell RNA sequencing combined with CRISPR perturbation allows simultaneous measurement of the delivered CRISPR guide and the full transcriptome state of individual primary human immune cells.