Genetic analysis of isoform usage in the human anti-viral response

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. Analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs for the same gene. Compared to eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. We used paired-end RNA-seq to profile the transcriptomes of primary MoDCs from healthy donors at rest (N = 99), and following stimulation with either recombinant interferon beta (IFNB1), a type 1 interferon that stimulates anti-viral effectors (N = 227), or influenza ΔNS1 (a strain engineered to maximize the type 1 interferon-induced response to infection by the deletion of a key virulence factor). Submitter declares that the raw data have been submitted to dbGaP (phs000815.v1.p1) because of patient privacy concerns.