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

IF 31.7 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-03-04 DOI:10.1038/s41588-025-02096-3

Alex Tokolyi, Elodie Persyn, Artika P. Nath, Katie L. Burnham, Jonathan Marten, Thomas Vanderstichele, Manuel Tardaguila, David Stacey, Ben Farr, Vivek Iyer, Xilin Jiang, Samuel A. Lambert, Guillaume Noell, Michael A. Quail, Diana Rajan, Scott C. Ritchie, Benjamin B. Sun, Scott A. J. 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

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Abstract

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 ). Integrative analyses of whole-blood gene expression and splicing QTLs with protein, metabolite and lipid QTLs from the same individuals shed light on the shared genetic architecture of molecular traits and health outcomes.

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution