The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes
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 ).
Authors
- Benjamin B. Sun (ORCID: https://orcid.org/0000-0001-6347-2281)
- David J. Roberts (ORCID: https://orcid.org/0000-0003-0648-6585)
- Alex Tokolyi (ORCID: https://orcid.org/0000-0003-4222-7484)
- Emanuele Di Angelantonio (ORCID: https://orcid.org/0000-0001-8776-6719)
- Daniel J. Gaffney (ORCID: https://orcid.org/0000-0002-1529-1862)
- Dirk S. Paul (ORCID: https://orcid.org/0000-0002-8230-0116)
- Michael A. Quail (ORCID: https://orcid.org/0000-0002-3861-0483)
- Xilin Jiang (ORCID: https://orcid.org/0000-0001-6773-9182)
- Artika P. Nath (ORCID: https://orcid.org/0000-0002-5688-2941)
- Ben W. Farr
- James E. Peters (ORCID: https://orcid.org/0000-0002-9415-3440)
- Emma E. Davenport (ORCID: https://orcid.org/0000-0002-8768-346X)
- John Danesh (ORCID: https://orcid.org/0000-0003-1158-6791)
- Thomas Vanderstichele
- Nicole Soranzo (ORCID: https://orcid.org/0000-0003-1095-3852)
- Samuel A. Lambert (ORCID: https://orcid.org/0000-0001-8222-008X)
- Elodie Persyn (ORCID: https://orcid.org/0000-0001-9104-1972)
- Scott C. Ritchie (ORCID: https://orcid.org/0000-0002-8454-9548)
- Michael Inouye (ORCID: https://orcid.org/0000-0001-9413-6520)
- Yu Xu (ORCID: https://orcid.org/0000-0002-7304-5045)
- Jonathan Marten (ORCID: https://orcid.org/0000-0001-6916-2014)
- Christopher D. Whelan (ORCID: https://orcid.org/0000-0003-0308-5583)
- Guillaume Noell (ORCID: https://orcid.org/0000-0002-0069-4933)
- Manuel Tardáguila (ORCID: https://orcid.org/0000-0001-7812-604X)
- Scott Thurston (ORCID: https://orcid.org/0000-0002-1657-9200)
- Katie L. Burnham (ORCID: https://orcid.org/0000-0001-8680-2933)
- Heiko Runz (ORCID: https://orcid.org/0000-0002-2133-7345)
- Adam S. Butterworth (ORCID: https://orcid.org/0000-0002-6915-9015)
- David Stacey (ORCID: https://orcid.org/0000-0002-9392-9235)
- Vivek Iyer
- Slavé Petrovski (ORCID: https://orcid.org/0000-0002-1527-961X)
- Diana Rajan
Institutions
- AstraZeneca (United Kingdom) (GB)
- Biogen (United States) (US)
- NHS Blood and Transplant (GB)
- Harvard University (US)
- Baker Heart and Diabetes Institute (AU)
- The University of Melbourne (AU)
- University of South Australia (AU)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- John Radcliffe Hospital (GB)
- British Heart Foundation (GB)
- AstraZeneca (Australia) (AU)
- AstraZeneca (Singapore) (SG)
- Human Technopole (IT)
- South Australian Health and Medical Research Institute (AU)
- Health Data Research UK (GB)
- Janssen (United States) (US)
- Austin Health (AU)
- Imperial College London (GB)
- BioMarin (United States) (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1038/s41588-025-02096-3
- Citations
- 17
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 29.08
Funders
- AstraZeneca
- Biogen
- BioMarin Pharmaceutical
- NHS Blood and Transplant
- Wellcome Trust
- Dell EMC
- Scottish Government
- European Federation of Pharmaceutical Industries and Associations
- National Institute for Health and Care Research
- British Heart Foundation
- Department of Health and Social Care
- European Commission
- Public Health Agency
- Chief Scientist Office, Scottish Government Health and Social Care Directorate
- NIHR BioResource
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- Science and Technology Facilities Council
- Health and Social Care Research and Development Division
- NIHR Cambridge Biomedical Research Centre