Nature genetics · 2025
The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes.
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Tokolyi Alex, Persyn Elodie, Nath Artika P, Burnham Katie L, Marten Jonathan, Vanderstichele Thomas, Tardaguila Manuel, Stacey David, Farr Ben, Iyer Vivek, Jiang Xilin, Lambert Samuel A, Noell Guillaume, Quail Michael A, Rajan Diana, Ritchie Scott C, Sun Benjamin B, Thurston Scott A J, Xu Yu, Whelan Christopher D, Runz Heiko, Petrovski Slavé, Gaffney Daniel J, Roberts David J, Di Angelantonio Emanuele, Peters James E, Soranzo Nicole, Danesh John, Butterworth Adam S, Inouye Michael, Davenport Emma E, Paul Dirk S
Аннотация
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 uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans ( https://IntervalRNA.org.uk ).