Genetic determinants of blood gene expression and splicing and their contribution to molecular phenotypes and health outcomes
Preprint
Abstract
Summary: The biological mechanisms through which most non-protein-coding genetic variants affect disease risk are unknown. To investigate the gene-regulatory cascades that ensue from these variants, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA-sequencing in 4,732 participants, and integrated these data with protein, metabolite and lipid QTLs in the same individuals. We identified cis -QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Using colocalization analysis, we identified 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 through statistical mediation, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at GWAS disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access and interactive resource of the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans ( https://IntervalRNA.org.uk ).Keywords
All Related Versions
- Published version: Nature Genetics, 57 (3), 616.
This publication has 74 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traitsNature Genetics, 2012
- Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analysesNature Protocols, 2012
- GCTA: A Tool for Genome-wide Complex Trait AnalysisThe American Journal of Human Genetics, 2011
- A scaling normalization method for differential expression analysis of RNA-seq dataGenome Biology, 2010
- Interleukin 7 receptor α chain ( IL7R ) shows allelic and functional association with multiple sclerosisNature Genetics, 2007
- GenABEL: an R library for genome-wide association analysisBioinformatics, 2007
- Variation in Antiviral 2′,5′-Oligoadenylate Synthetase (2′5′AS) Enzyme Activity Is Controlled by a Single-Nucleotide Polymorphism at a Splice-Acceptor Site in the OAS1 GeneThe American Journal of Human Genetics, 2005
- Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptorCytokine, 1992
- Cloning of the human and murine interleukin-7 receptors: Demonstration of a soluble form and homology to a new receptor superfamilyCell, 1990