Genetic determinants of monocyte splicing are enriched for disease susceptibility loci including for COVID-19

Abstract

Insights into variation in monocyte context-specific splicing and transcript usage are limited. We have performed paired gene and transcript QTL mapping across distinct immune states using RNA-seq of monocytes isolated from a cohort of 185 healthy Europeans incubated alone or in the presence of IFNγ or lipopolysaccharide (LPS). We identify regulatory variants to 5,749 genes and 8,727 transcripts, with 291 context-specific tQTL colocalising with GWAS loci (PP.H4 > 0.8). Notable disease relevant associations (PP.H4 > 0.99) include IFNγ specific tQTL 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. Assessment of DNA methylation from the same cells demonstrated frequent overlap between mQTL and causal context-specific eQTL, frequently permitting inference of the direction of effect. Finally, we identify a subset of eQTL that uncouple genes from proximally acting regulatory networks, creating ‘co-expression QTL’ (coExQTL) with differential 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.