Novel insight into the etiology of ischemic stroke gained by integrative transcriptome-wide association study
Jung, J.; Lu, Z.; de Smith, A. J.; Mancuso, N.
Show abstract
Stroke, characterized by sudden neurological deficits, is the second leading cause of death worldwide. Although genome-wide association studies (GWAS) have successfully identified many genomic regions associated with ischemic stroke (IS), the genes underlying risk and their regulatory mechanisms remain elusive. Here, we integrate a large-scale GWAS (N=1,296,908) for IS together with mRNA, splicing, enhancer RNA (eRNA) and protein expression data (N=11,588) from 50 tissues. We identify 136 genes/eRNA/proteins associated with IS risk across 54 independent genomic regions and find IS risk is most enriched for eQTLs in arterial and brain-related tissues. Focusing on IS-relevant tissues, we prioritize 9 genes/proteins using probabilistic fine-mapping TWAS analyses. In addition, we discover that blood cell traits, particularly reticulocyte cells, have shared genetic contributions with IS using TWAS-based pheWAS and genetic correlation analysis. Lastly, we integrate our findings with a large-scale pharmacological database and identify a secondary bile acid, deoxycholic acid, as a potential therapeutic component. Our work highlights IS risk genes/splicing-sites/enhancer activity/proteins with their phenotypic consequences using relevant tissues as well as identify potential therapeutic candidates for IS.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- The genetic and phenotypic correlates of mtDNA copy number in a multi-ancestry cohort 95%
- Evaluation of imputation performance of multiple reference panels in a Pakistani population 93%
- Multivariate adaptive shrinkage improves cross-population transcriptome prediction for transcriptome-wide association studies in underrepresented populations 93%
Similar papers in this journal
- Profiling genetically driven alternative splicing across the Indonesian Archipelago 94%
- Single-cell transcriptome-wide Mendelian randomization and colocalization analyses uncover cell-specific mechanisms in atherosclerotic cardiovascular disease 94%
- A unified framework for cell-type-specific eQTLs prioritization by integrating bulk and scRNA-seq data 94%
Similar papers in this journal
- Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex 95%
- Leveraging genomic diversity for discovery in an EHR-linked biobank: the UCLA ATLAS Community Health Initiative 95%
- Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance 94%
Similar papers in this journal
- Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome 95%
- Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms 95%
- SUMMIT: An integrative approach for better transcriptomic data imputation improves causal gene identification 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.