Genetic variants within silencer elements contribute to human blood cell traits

However, assigning regulatory functions to causal variants remains challenging, historical efforts have largely focused on promoters and enhancers, often overlooking the regulatory impact of silencers. In this study, we performed high-throughput screening to characterize changes in potential silencer activities within 14,720 fine-mapped causal non-coding single-nucleotide polymorphisms (SNPs) associated with 15 diverse blood traits.

We have prioritized 805 blood trait-associated non-coding SNPs link to changes in putative silencer activity (425 loss-of-function and 380 gain-of-function). Using targeted mutagenesis in orthogonal episomal reporter assays and endogenous knock-in via CRISPR-Cas9 editing, we validated the allelic imbalances in silencer activity of identified silencer-disruptive variants. We demonstrated that a silencer-disruptive variant rs2857078 can impair red blood cell maturation and hemoglobin synthesis using an in vitro K562 erythroid differentiation model.