Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection

While the impact of common genetic variants on transcript abundance in response to cellular stimuli has been analyzed in depth, less is known about how stimulation modulates the genetic control of isoform usage. Using RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to viral infection or stimulation with Type 1 interferon. We identified more than a thousand single nucleotide polymorphisms associated with 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, and depleted of upstream sequences. In five loci, they provide a possible mechanism of action underlying DNA variants associated with immune-related disorders. Among these five is the ERAP2 locus, where the major haplotype is under balancing selection and associated with Crohn9s disease risk. At baseline and following Type 1 interferon stimulation, the major haplotype is associated with absence of ERAP2 expression; but in response to influenza infection, the major haplotype results in the expression of two previously uncharacterized, alternatively transcribed, spliced and translated short isoforms. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in the innate immune response, and in the case of ERAP2, may confer a historical fitness advantage in response to virus, but increase risk for autoimmunity in the modern environment.