Single-cell splicing analysis with ISSAC links cell type specific and cell state-dependent sQTLs to neurological disorders

Single-cell RNA sequencing enables comprehensive profiling of gene expression and splicing at cellular resolution, revealing cell type-specific and cell state-dependent regulation (variation within cell types based on their functional states). While genetic studies of expression (eQTLs) in single cells are well established, the genetic regulation of alternative splicing in single cells remains challenging. Existing single-cell splicing QTL (sQTL) studies perform pseudobulk aggregation using bulk analysis methods, which reduces power to detect cell type-specific sQTLs and cannot capture cell state-dependent splicing regulation. Here, we introduce ISSAC to directly quantify metacell-level spli