The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes

SUMMARY Infectious diseases (ID) represent a significant proportion of morbidity and mortality across the world. Host genetic variation is likely to contribute to ID risk and downstream clinical outcomes, but there is a need for a genetics-anchored framework to decipher molecular mechanisms of disease risk, infer causal effect on potential complications, and identify instruments for drug target discovery. Here we perform transcriptome-wide association studies (TWAS) of 35 clinical ID traits in a cohort of 23,294 individuals, identifying 70 gene-level associations with 26 ID traits. Replication in two large-scale biobanks provides additional support for the identified associations. A phenome-scale scan of the 70 gene-level associations across hematologic, respiratory, cardiovascular, and neurologic traits proposes a molecular basis for known complications of the ID traits. Using Mendelian Randomization, we then provide causal support for the effect of the ID traits on adverse outcomes. The rich resource of genetic information linked to serologic tests and pathogen cultures from bronchoalveolar lavage, sputum, sinus/nasopharyngeal, tracheal, and blood samples (up to 7,699 positive pathogen cultures across 92 unique genera) that we leverage provides a platform to interrogate the genetic basis of compartment-specific infection and colonization. To accelerate insights into cellular mechanisms, we develop a TWAS repository of gene-level associations in a broad collection of human tissues with 79 pathogen-exposure induced cellular phenotypes as a discovery and replication platform. Cellular phenotypes of infection by 8 pathogens included pathogen invasion, intercellular spread, cytokine production, and pyroptosis. These rich datasets will facilitate mechanistic insights into the role of host genetic variation on ID risk and pathophysiology, with important implications for our molecular understanding of potentially severe phenotypic outcomes. HIGHLIGHTS Atlas of genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) results for 35 clinical infectious disease (ID) phenotypes, with genome-wide and transcriptome-wide significant results for 13 and 26 clinical ID traits, respectively Phenome-scale scan of ID-associated genes across 197 hematologic, respiratory, cardiovascular, and neurologic traits, facilitating identification of genes associated with known complications of the ID traits Mendelian Randomization analysis, leveraging naturally occurring DNA sequence variation to perform “randomized controlled trials” to test the causal effect of ID traits on potential outcomes and complications A genomic resource of TWAS associations for 79 pathogen-induced cellular traits from High-throughput Human in vitrO Susceptibility Testing (Hi-HOST) across 44 tissues as a discovery and replication platform to enable in silico cellular microbiology and functional genomic experiments