Our new preprint proposing a new single-cell based framework for transcriptome-wide association studies

Our new preprint proposes a single-cell transcriptome-wide association study (TWAS) pipeline 🧬

While thousands of genomic loci have been associated with human disease, it remains a struggle to link them to causal genes and mechanisms that can inform druggable target discovery. TWAS links genomic loci to gene expression promising to bridge this gap. However, traditional methods rely on bulk expression data that lack single-cell resolution.

💡 In this preprint we propose a pipeline that integrates single-cell eQTLs to detect cell-specific mechanisms driving genetic predisposition to human disease.

𝐇𝐢𝐠𝐡𝐥𝐢𝐠𝐡𝐭𝐬:
👉 Our pipeline combines discovery and replication Mendelian randomization and colocalization analyses
👉 As a case study, we implemented it on immune cell eQTLs and atherosclerotic cardiovascular disease (CVD)
👉 Major information gains as compared to bulk TWAS despite the much smaller sample sizes of single-cell eQTL datasets — <20% of signals in single-cell TWAS were detectable in whole blood bulk TWAS
👉 We uncovered 17 robust signals that provide mechanistic insights about expression of specific genes in specific immune cells that underlie genomic loci for atherosclerotic CVD
👉 A signal for 𝘓𝘐𝘗𝘈 expression in monocytes was consistent across different atherosclerotic traits and guided downstream analyses in human atherosclerotic plaques

This analytical pipeline could potentially inform drug target selection for cell-tailored therapeutics (e.g. RNA-based therapies)❗

Great work by amazing PhD student Anushree Ray❗

🔗Link to preprint: https://www.medrxiv.org/content/10.1101/2024.12.19.24319316v1