SRP319208 PRJNA728702 GSE174188 Multiplexed scRNA-seq reveals the cellular and genetic correlates of systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and cell states associated with SLE remains incomplete. We profiled over 1.2 million PBMCs (162 cases, 99 controls) with multiplexed single-cell RNA-seq (mux-seq). Cases exhibited prominent expression of type-1 interferon-stimulated genes (ISG) in monocytes, reduction of naïve CD4+ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH+ CD8+ T cells. Cell-type-specific expression features accurately predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data, mapping cell-type-specific cis-eQTLs and linked known and novel SLE-associated variants to cell-type-specific gene expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE. Overall design: Examination of 1.2 million PBMCs in 162 SLE donors and 99 healthy individuals to find cellular and genetic correlates of SLE. GSE174188 pubmed 35389781 pubmed 36171194