NY Genome Center Team Develops Method for Target Gene, Pathway Discovery at GWAS Loci

While genome-wide association studies (GWASs) have identified thousands of genetic variants associated with disease outcomes and disease-related phenotypes, these associations are nearly always found in noncoding regions, making their target genes and functions difficult to identify. By combining GWAS with CRISPR gene editing and single-cell sequencing, a team led by scientists from the New York Genome Center has developed a method to overcome this challenge. As reported in Science this week, the approach — dubbed STING-Seq — involves prioritizing candidate cis-regulatory elements via functional annotation and overlap with fine-mapped GWAS variants. Pooled CRISPR inhibition, single-cell RNA sequencing, and cell surface protein measurements are then used to test for gene regulatory function. The researchers demonstrate STING-Seq by applying it to discover 124 cis-target genes of 91 noncoding blood trait GWAS loci. For a subset of validated cis-regulatory elements, they also inserted specific GWAS variants using base editing STING-Seq, identifying noncoding GWAS variants with causal effects on target gene expression. STING-Seq, its developers write, provides a roadmap to address variant-to-function challenges and identify target genes for GWAS loci in a high-throughput fashion.