Variant-to-function dissection of rare non-coding GWAS loci with high impact on blood traits

Tardaguila, M.; Soranzo, N.; Von Schiller, D.; Colombo, M.; Gori, I.; Coomber, E. L.; Vanderstichele, T.; Benaglio, P.; Chiereghin, C.; Gerety, S. S.; Vuckovic, D.; Landini, A.; Clerici, G.; Albers, P. K.; Walter, K.; Kundu, K.; Pirastu, N.; Ray-Jones, H.; Burnham, K. L.; Tokolyi, A.; Persyn, E.; Spivakov, M.; Watt, S.; Inouye, M.; Paul, D. S.; Davenport, E.; Sahlen, P.; Sankaran, V. G.

doi:10.1101/2024.08.05.606572

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bioRxiv · 10.1101/2024.08.05.606572

Variant-to-function dissection of rare non-coding GWAS loci with high impact on blood traits

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Abstract

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.

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Tardaguila, M., Soranzo, N., Von Schiller, D., Colombo, M., Gori, I., Coomber, E. L., Vanderstichele, T., Benaglio, P., Chiereghin, C., Gerety, S. S., Vuckovic, D., Landini, A., Clerici, G., Albers, P. K., Walter, K., Kundu, K., Pirastu, N., Ray-Jones, H., Burnham, K. L., Tokolyi, A., Persyn, E., Spivakov, M., Watt, S., Inouye, M., Paul, D. S., Davenport, E., Sahlen, P., Sankaran, V. G.. 2024-08-05. Variant-to-function dissection of rare non-coding GWAS loci with high impact on blood traits. https://doi.org/10.1101/2024.08.05.606572

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