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Genetic variants within silencer elements contribute to human blood cell traits

ABSTRACT: Genome-wide association studies (GWAS) have identified numerous non-coding loci associated with human complex traits and diseases. 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. To prioritize pathogenic variants within silencer elements, we trained a machine learning model using evolutionary conservation metrics and single-cell chromatin accessibility profiles across the hematopoietic hierarchy. Taken together, our study underscores the importance of investigating functions of silencer variants in post-GWAS functional studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE347432 | GEO | 2026/09/22

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE347432_K562_RNAseq-rs2857078-KI-vs-control.diffexp.tsv.gz	Tabular
	GSE347432_K562_RNAseq-rs4808806-KI-vs-control.diffexp.tsv.gz	Tabular
	GSE347432_Merged_ReSE_screen_count.txt.gz	Txt
	GSE347432_RNAseq_gene_exp.tsv.gz	Tabular

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