Massively Parallel Reporter Assay of Rare non-coding variants with high impact in blood traits

Understanding the function of genetic variants associated with human traits and diseases remains a significant challenge. Here we combined analyses based on natural genetic variation and genetic engineering to dissect the function of 94 non-coding variants associated with haematological traits. We describe 22 genetic variants impacting haematological variation through gene expression. Further, through in-depth functional analysis, we illustrate how a rare, non-coding variant near the CUX1 transcription factor impacts megakaryopoiesis through modulation of the CUX1 transcriptional cascade. Collectively, our findings enhance the functional interpretation of genetic association studies and advance understanding of how non-coding variants contribute to blood and immune system variation.