Two decades of Genome Wide Association Studies (GWAS) have yielded hundreds of thousands of robust genetic associations to human complex traits and diseases. Nevertheless, the dissection of the functional consequences of variants lags behind, especially for non-coding variants (RNVs). Here we have characterised a set of rare, non-coding variants with large effects on haematological traits by integrating (i) a massively parallel reporter assay with (ii) a CRISPR/Cas9 screen and (iii)in vivogene expression and transcript relative abundance analysis of whole blood and immune cells. After extensive manual curation we identify 22 RNVs with robust mechanistic hypotheses and perform an in-depth characterization of one of them, demonstrating its impact on megakaryopoiesis through regulation of theCUX1transcriptional cascade. With this work we advance the understanding of the translational value of GWAS findings for variants implicated in blood and immunity.