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Genetic variants within silencer elements contribute to human blood cell traits

Tan, M.; van Weerd, J.; Yavas, A.; Pang, B.

2025-01-14 genetics
10.1101/2025.01.13.632723 bioRxiv
Show abstract

Genome-wide association studies (GWAS) have identified numerous non-coding loci associated with human complex traits and diseases. However, assigning the functional impacts to the underlying variants remains challenging. In this study, we performed high-throughput ReSE screening to characterize the effects of 14,720 fine-mapped causal non-coding SNPs associated with 15 diverse blood traits on the potential silencer activity. By prioritizing non-coding variants that confer allelic imbalances in silencer activity, we identified epigenomic signatures of silencer-related variants and assessed their heritability contributions to specific blood traits. We conducted mechanistic studies on individual silencer variants and characterized the transcriptional factors (TF) that may recognize the silencer elements harboring the blood traits-related GWAS variants. We showed the silencer activity of GWAS variants rs4808806 which is related to red blood cell distribution width (RDW) and rs10758656 which is associate with mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) traits. Our study underscores the importance of investigating the silencer-activity-related variants in post-GWAS functional studies.

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