Expression QTLs in single-cell sequencing data

Abstract Single nucleotide polymorphisms (SNPs) are important drivers of gene expression variation and downstream phenotypes including disease risk. Single-cell RNA-sequencing (scRNA-seq) allows an unprecedented exploration of cell-type specific associations between gene expression levels and genotypes, but current methods rely on pseudobulk approaches that use composite expression values across cells and often use summary statistics within cell types, ignoring information across cell types and assuming cell type labels are accurate. Here, we extend our method, telescoping bimodal latent Dirichlet allocation (TBLDA), that identifies covarying genotypes and gene expression values when the matching from samples to cells is not one-to-one in order to allow cell-type label agnostic discovery of eQTLs in noncomposite scRNA-seq data. In particular, we add GPU-compatibility, sparse priors, and amortization to enable fast inference on large-scale scRNA-seq data. We apply single-cell TBLDA (scTBLDA) to 400K cells from 119 individuals with systemic lupus erythematosus and examine properties of features from each modality across the estimated latent factors. We use linked genes and SNPs to identify 205 cis-eQTLS, 66 trans-eQTLs, and 53 cell type proportion QTLs, which we then compare against prior studies of immune-cell eQTLs. Our results demonstrate the ability of scTBLDA to identify genes involved in cell-type specific regulatory processes associated with SNPs in single-cell data.