Pulse Brain · Growing Health Evidence Index
Peer-reviewed

The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes

Alex Tokolyi, Elodie Persyn, Artika P. Nath, Katie L. Burnham, Jonathan Marten, Thomas Vanderstichele, Manuel Tardáguila, David Stacey, Ben W. Farr, Vivek Iyer, Xilin Jiang, Samuel A. Lambert, Guillaume Noell, Michael A. Quail, Diana Rajan, Scott C. Ritchie, Benjamin B. Sun, Scott Thurston, Yu Xu, Christopher D. Whelan, Heiko Runz, Slavé Petrovski, Daniel J. Gaffney, David J. Roberts, Emanuele Di Angelantonio, James E. Peters, Nicole Soranzo, John Danesh, Adam S. Butterworth, Michael Inouye, Emma E. Davenport, Dirk S. Paul

Nature Genetics · 2025

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Summary

The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncove

Source type
Peer-reviewed study
DOI
10.1038/s41588-025-02096-3
Catalogue ID
SNmois84py-d83660
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