Genetic determinants of monocyte splicing are enriched for disease susceptibility loci.

Insights into variation in monocyte context-specific splicing and transcript usage are limited. Here, we perform paired gene and transcript QTL mapping across distinct immune states using RNA sequencing data of monocytes isolated from a cohort of 185 healthy Europeans incubated alone or in the presence of interferon gamma (IFN-γ) or lipopolysaccharide (LPS). We identify regulatory variants for 5749 genes and 8727 transcripts, with 291 context-specific transcript QTL colocalizing with GWAS loci. Notable disease relevant associations include IFN-γ specific transcript QTL at COVID-19 severity locus rs10735079, where allelic variation modulates context-specific splicing of OAS1, and at rs4072037, a risk allele for gastro-esophageal cancer, which associates with context-specific splicing of MUC1. We use DNA methylation data from the same cells to demonstrate overlap between methylation QTL and causal context-specific expression QTL, permitting inference of the direction of effect. Finally, we identify a subset of expression QTL that uncouple genes from proximally acting regulatory networks, creating 'co-expression QTL' with different allele-specific correlation networks. Our findings highlight the interplay between context and genetics in the regulation of the monocyte gene expression and splicing, revealing putative mechanisms of diverse disease risk alleles including for COVID-19 and cancer.