Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants reside on STF and not MTF motifs, perturbing DNA binding by various STFs (BMP/TGF-β-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Analyses of engineered human blood cells and expression quantitative trait loci verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC-trait-associated variants that reside on transcription-factor-binding sequences fall in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.

全基因组关联研究确定与人类特征和疾病相关的基因组变异。大多数性状相关变异位于细胞类型特异性增强子内，但控制表型变异的分子机制尚不清楚。在这里，我们展示了许多与红细胞 (RBC) 性状相关的增强子变体映射到由谱系特异性主转录因子 (MTF) 和响应细胞外信号的信号转录因子 (STF) 共同结合的增强子。大多数增强子变体存在于 STF 而不是 MTF 基序上，干扰了各种 STF（BMP/TGF-β 定向 SMAD 或 WNT 诱导的 TCF）的 DNA 结合并影响靶基因表达。对工程人类血细胞和表达数量性状基因座的分析证实，STF 结合中断会导致基因表达改变。我们的研究结果表明，大多数位于转录因子结合序列上的 RBC 性状相关变体属于 STF 靶序列，这表明 RBC 性状的表型变异可能源于对细胞外刺激的反应性改变。