An atlas of genetic variation for linking pathogen-induced cellular traits to human disease

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with disease. To facilitate moving from associations to disease mechanisms, we leveraged the role of pathogens in shaping human evolution with the Hi-HOST Phenome Project (H2P2): a catalog of cellular GWAS comprised of 79 phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance (p<5x10-8) for phenotypes ranging from pathogen replication to cytokine production. Combining H2P2 with clinical association data on 83,717 patients from the eMERGE Network and experimental validation revealed evidence for mechanisms and connections with diseases. We identified a SNP near CXCL10 as a cis-cytokine-QTL and risk factor for inflammatory bowel disease. A SNP in ZBTB20 demonstrated pleiotropy, likely through suppression of multiple target genes, and was associated with viral hepatitis. Data are in an H2P2 web portal to facilitate interpreting human genome variation through the lens of cell biology. Three human Huh7s' mRNA profiles from non-target, ZBTB20 siRNA Chlamydia infection were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000/2500 platform.