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Discovery of target genes and pathways of blood trait loci using pooled CRISPR screens and single cell RNA sequencing

ABSTRACT: The majority of variants associated with complex traits and common diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown regulatory effects. By leveraging ancestrally diverse biobank-scale GWAS data, massively parallel CRISPR screens and single cell transcriptomic and proteomic sequencing, we discovered target genes of noncoding variants for blood trait loci. For 91 GWAS loci, we identified 124 target genes in cis, which were often — but not always — the closest genes to the fine-mapped variant. Using precise variant insertion via base editing, we connect specific variants with gene expression changes. We also identified trans-effect networks of noncoding loci when cis target genes encoded transcription factors or microRNAs, such as GFI1B and miR-142. Trans-regulatory networks were themselves enriched for fine-mapped GWAS variants, demonstrating polygenic contributions to complex traits. Co-expression clustering of GFI1B trans-target genes identifies gene networks specific to different blood cell fates and differentiation stages. This platform will enable massively parallel assays to characterize the target genes and mechanisms of human noncoding variants in both cis and trans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171452 | GEO | 2021/04/08

REPOSITORIES: GEO

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