Single-cell RNA-seq reveals the cell-type-specific molecular and genetic associations to lupus

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled over 1.2 million PBMCs (162 cases, 99 controls) with multiplexed single-cell RNA-sequencing (mux-seq). Cases exhibited elevated 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 predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell-type-specific cis-eQTLs and link SLE-associated variants to cell-type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.