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bioRxiv · 10.64898/2026.03.03.708783

Genome-wide maps of transcription factor footprints identify noncoding variants rewiring gene regulatory networks with varTFBridge

Lin, J.·Dong, W.·Zhang, J.·Xie, C.·Jing, X.·Zhao, J.·Ma, K.·Kang, H.·Jiang, Y.·Xie, X. S.·Zhao, Y.
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Abstract

Genome-wide association studies have identified millions of noncoding loci linked to human traits, yet how these variants alter gene regulation remains a major challenge, particularly for rare variants where whole-genome sequencing cohorts and high-resolution functional annotations remain limited. Here we show that single-molecule deaminase footprinting (FOODIE) in K562 cells captures up to 103-fold heritability enrichment for erythroid traits despite covering 0.12% of the genome. We introduce varTFBridge, integrating FOODIE footprinting with AlphaGenome variant effect prediction to identify causal noncoding variants altering transcription factor (TF)-mediated regulation. Applied to 490,640 UK Biobank genomes across 13 erythrocyte traits, varTFBridge prioritises 113 high-confidence regulatory variants (104 common, 9 rare), encompassing 2,173 linkages along the variant-TF binding- gene-trait cascade across 64 TFs and 108 genes. varTFBridge recapitulates rs112233623 and resolves its mechanism: GATA1/TAL1 co-binding disruption at a CCND3 enhancer altering red blood cell count and volume.

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Lin, J., Dong, W., Zhang, J., Xie, C., Jing, X., Zhao, J., Ma, K., Kang, H., Jiang, Y., Xie, X. S., Zhao, Y.. 2026-03-05. Genome-wide maps of transcription factor footprints identify noncoding variants rewiring gene regulatory networks with varTFBridge. https://doi.org/10.64898/2026.03.03.708783

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