Abstract
Transcriptome-wide association studies (TWAS) have been widely used to prioritize relevant genes for diseases. Current methods for TWAS test gene-disease associations at bulk tissue or cell-type-specific pseudobulk level, which do not account for the heterogeneity within cell types. We present TWiST, a statistical method for TWAS analysis at cell state resolution using single-cell expression quantitative trait loci (eQTL) data. Our method uses pseudotime to represent cell states and models the effect of gene expression on trait as a continuous pseudotemporal curve. Therefore, it allows flexible hypothesis testing of global, dynamic, and nonlinear effects. Through simulation studies and real data analysis, we demonstrated that TWiST leads to significantly improved power compared to pseudobulk methods that ignores heterogeneity due to cell states. Application to the OneK1K study identified hundreds of genes with dynamic effects on autoimmune diseases along the trajectory of immune cell differentiation. TWiST presents great promise to understand disease genetics using single-cell eQTL studies.