Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens

作者：John A. Morris, Christina M. Caragine, Zharko Daniloski, Júlia Domingo, Timothy Barry, Lu Lu, Kyrie E. Davis, M. Ziosi, Dafni A. Glinos, S. Hao, Eleni P. Mimitou, Peter Smibert, K. Roeder, Eugene Katsevich, T. Lappalainen, Neville E. Sanjana · 发表于：Science · 年份：2023 · DOI：10.1126/science.adh7699 · 被引用次数：173 · 研究领域：Medicine

Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown effects. Using ancestrally diverse, biobank-scale GWAS data, massively parallel CRISPR screens, and single-cell transcriptomic and proteomic sequencing, we discovered 124 cis-target genes of 91 noncoding blood trait GWAS loci. Using precise variant insertion through base editing, we connected specific variants with gene expression changes. We also identified trans-effect networks of noncoding loci when cis target genes encoded transcription factors or microRNAs. Networks were themselves enriched for GWAS variants and demonstrated polygenic contributions to complex traits. This platform enables massively parallel characterization of the target genes and mechanisms of human noncoding variants in both cis and trans. Description Editor’s summary Genome-wide association studies (GWASs) identify links between individual gene variants and various traits and diseases. Unfortunately, the findings from these studies cannot be used to determine whether the gene variants associated with a disease directly cause the condition or just happen to be located near biologically relevant genes or regulatory regions. Most of the variants identified through GWASs are located in noncoding regions of the genome, further increasing the difficulty of interpretation. A workflow developed by Morris et al. addresses this problem by using CRISPR...