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

Abstract

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.

The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

“…However, genetic susceptibility confers risk to all these preceding factors as well as to HC directly. Thus, understanding the pleiotropic effect of genes on both risk factors and development of HC is needed and requires highly detailed phenomics analysis [33]. Here, we summarize all genetic studies of human HC across the age spectrum, including discussion of animal models of HC only as corroborating findings of genes and pathways identified in humans where there is a reasonable degree of evolutionary conservation.…”

The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

“…The copyright holder for this preprint this version posted December 4, 2023. ; https://doi.org/10.1101/2023.12.03.23299322 doi: medRxiv preprint genetic susceptibility confers risk to all these preceding factors as well as to HC directly. Thus, understanding the pleiotropic effect of genes on both risk factors and development of HC is needed and requires highly detailed phenomics analysis [33]. Here, we summarize all genetic studies of human HC, including discussion of animal models of HC only as corroborating findings of genes and pathways identified in humans where there is a reasonable degree of evolutionary conservation.…”

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

“…22,23 Covariates for logistic regression models to identify IA-associated single-nucleotide polymorphisms (SNPs) included age, sex, and the first 5 principal components as previously described. 24 Genome-wide statistical significance was defined after Bonferroni correction for the total number of SNPs tested (P ≤ 5.0 × 10 À8 ) as previously described. 25 Genome-wide significant loci were defined based on genomic positions within 500 kb from the sentinel variant.…”