Integrating natural and engineered genetic variations to decode regulatory influence on 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 hematological traits. We describe 22 genetic variants impacting hematological 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 the 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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Publication Details

Journal
Cell Reports
Published
2026-02-01
DOI
https://doi.org/10.1016/j.celrep.2026.116937
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
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article

Integrating natural and engineered genetic variations to decode regulatory influence on blood traits

Ilaria Gori, Arianna Landini, Paola Benaglio, M. Colombo et al.
Cell Reports
Genetic Associations and Epidemiology
article

Integrating natural and engineered genetic variations to decode regulatory influence on blood traits

Ilaria Gori, Arianna Landini, Paola Benaglio, M. Colombo, Giuditta Clerici, Helen Ray-Jones, Thomas Vanderstichele, Paul Dirk, Dominique Von Schiller, Elodie Persyn, Chiara Chiereghin, Manuel Tardáguila, Aurora Casiraghi, Pelin Sahlén, Michael Inouye, Patrick Albers, Nicola Pirastu, Katie L. Burnham, Klaudia Walter, Kousik Kundu, Dragana Vuckovic, Stephen Watt, Mikhail Spivakov, Emma E. Davenport, Eve L. Coomber, Alex Tokolyi, Vijay G. Sankaran
article en

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 hematological traits. We describe 22 genetic variants impacting hematological 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 the 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.

Cell ReportsVol. 45(2)
Boston Children's Hospital (US), Harvard University (US), University of Cambridge (GB), Science for Life Laboratory (SE), Wellcome Sanger Institute (GB), British Heart Foundation (GB), National Institute for Health and Care Research (GB), Human Technopole (IT), Dana-Farber Cancer Institute (US), MRC London Institute of Medical Sciences (GB), Imperial College London (GB), KTH Royal Institute of Technology (SE)
Openalex Percentile: Top 64%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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