Single-cell transcriptome-wide Mendelian randomization and colocalization reveal cell-specific mechanisms in systemic...

SLE is a multifactorial autoimmune disease with complex genetic architecture and immune cell involvement. While genome-wide association studies (GWAS) have identified numerous risk loci, most are non-coding, making it challenging to pinpoint causal eGenes [genes with expression quantitative trait loci (eQTLs)] and therapeutic targets.

We integrated single-cell expression quantitative trait loci (sc-eQTL) data from 14 human immune cell types with Mendelian randomization (MR) and Bayesian colocalization analyses to identify eGenes causally associated with SLE. We applied phenome-wide association studies (PheWAS) to assess potential off-target effects of candidate eGenes and used DrugBank to identify existing drugs targeting these eGenes.

MR analysis identified 62 eGenes with significant causal effects on SLE across diverse immune cell types. Colocalization analysis prioritized eight eGenes with strong evidence of shared genetic regulation with SLE (PP.H4 >80%), including BLK (B lymphoid tyrosine kinase), RNF145 (Ring Finger Protein 145), FAM167A (Family with Sequence Similarity 167 Member A) and VRK3 (Vaccinia-Related Kinase 3). PheWAS analyses revealed few significant associations with non-immune traits for most candidate eGenes, suggesting low risk of adverse effects. Notably, BLK is a known target of fostamatinib and zanubrutinib, although its increased expression was protective, highlighting potential risks of inhibition in SLE.

This study demonstrates the utility of integrating sc-eQTL, MR and colocalization analyses to identify immune cell-specific causal eGenes in SLE. The findings offer new insights into disease mechanisms and highlight promising, low-risk therapeutic targets for precision drug development.