Genome-wide association of expression response of primary immune cells identifies novel cis and trans loci specific to distinct pathogen responses. C. Ye1, M. Lee1,2,5,7, A. C. Villani1, T. Raj1,2,3, W. Li1,5, T. M. Eisenhaure1,5, S. H. Imboywa3, P. I. Chipendo3, K. Rothamel4, K. Raddassi3, M. H. Lee3, I. Wood3, C. McCabe1, B. E. Stranger6,10, C. O. Benoist4, P. L. De Jager1,2,3, A. Regev1,8,9, N. Hacohen1,2,5, Immunological Variation Consortium 1) Broad Institute, Cambridge, MA; 2) Harvard Medical School, Boston, MA; 3) Department of Neurology, Brigham and Women's Hospital, Boston, MA; 4) Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA; 5) e, Massachusetts General Hospital, Boston, MA; 6) Section of Genetic Medicine, University of Chicago, Chicago, IL; 7) Harvard-MIT Healthy Sciences and Technology, Boston, MA; 8) Howard Hughes Medical Institute, Chevy Chase, MD; 9) Department of Biology, Massachusetts Institute of Technology, Cambridge, MA; 10) Institute of Genomics and Systems Biology, University of Chicago.

   The rising prevalence of many chronic autoimmune diseases suggests that the interaction between genetic variations in innate immune genes and their environment may play a role in defining disease pathogenesis. While much heterogeneity exists in environmental components in natura, which is often hard to assess systematically, we can study variant-environment interactions by stimulating immune cells with well-defined and controlled pathogen input, and subsequently measure the response as the output. To leverage this approach, we performed a systematic study aimed at identifying expression response quantitative trait loci (reQTLs) in anti-bacterial and anti-viral immune responses. Using a 415-gene signature, we profiled the response of primary monocyte-derived dendritic cells (MoDCs) activated by lipopolysaccharide (LPS), influenza and IFN stimulation (a shared downstream cytokine of the anti-viral and anti-bacterial pathways) in 560 individuals of 3 ethnicities. We identified 119/415 (29%) genes to have significant (FDR < 0.05) cis-reQTLs, most of which are shared between stimuli due to a common IFN response. Using imputation, multiethnic meta-analysis and ENCODE annotations, we identified potential causal variants that perturb the canonical interferon-stimulated response element (ISRE) in three immune response genes. These reQTLs were validated by measuring the ability of each allele to drive reporter gene expression in IFN-stimulated cells. For one locus we show differential IFN-stimulated binding of a critical transcription factor to the major and minor variants of the ISRE in vitro. We identified GWAS variants in 32 unique genes to be cis-reQTLs, including associations to Crohns and SLE variants, under influenza and IFN stimulation. These SLE variants were also associated in trans with known downstream targets (interferon stimulated genes) under influenza infection, which we successfully validated through functional experimentations. Taken together, we demonstrate widespread expression response QTLs in core innate immune response programs to bacteria and viruses. By studying stimulated cells with defined environmental input and leveraging naturally occurring genetic variations, we identified known and new biological relationships in innate immune pathways that have important implications in defining key mechanisms involved in immune disease.

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