| Title: | The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes |
| Journal: | Nature Genetics |
| Published: | 4 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40038547/ |
| DOI: | https://doi.org/10.1038/s41588-025-02096-3 |
Publication 15653
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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).</p>
32 Authors
- 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
2 Applications
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
| 65851 | Large-scale proteomic profiling to facilitate genetics-guided drug discovery and precision medicine: The UK Biobank - Pharma Proteomics Project (UKB-PPP) |
Enabling scientific discoveries that improve human health