The Awesome Power of Human Genetics of Infectious Disease

Gibbs, Kyle D.; Schott, Benjamin H.; Ko, Dennis C.

doi:10.1146/annurev-genet-080320-010449

Cited by 10 publications

(10 citation statements)

References 154 publications

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“…An advantage of the Diversity Outbred mouse population is that infection with M. tuberculosis induces phenotypes that are rare in common laboratory inbred strains of mice [15][16][17]. Further, a growing body of evidence shows similarities in M. tuberculosis-infected Diversity Outbred mice and humans in biomarkers, gene expression signatures, and BCG vaccination [38,39,67,68,91].…”

Section: Discussionmentioning

confidence: 99%

“…The disease is usually restricted to the lungs and is characterized by granuloma necrosis and cavitation, neutrophilic infiltration, and cachexia [76,77]. The genetic basis of pulmonary TB is complex and not attributable to single-gene defects that cause severe immune deficiency (i.e., Mendelian susceptibility to mycobacterial disease does not explain pulmonary TB) [15,[78][79][80][81][82][83]. Although genomewide association studies have identified loci, gene candidates, and SNPs associated with increased or decreased odds ratios for pulmonary TB, only a few (e.g., Ipr1/SP110b and HLA variants/I-A Major Histocompatibility genes) have been validated [16,[84][85][86][87][88][89][90].…”

Section: Discussionmentioning

confidence: 99%

“…The variable responses to M. tuberculosis and lack of single genetic defects in most patients indicate a complex genetic basis for pulmonary TB, and this has been investigated by linkage association mapping, genome-wide association studies, and other methods, recently reviewed [14][15][16][17]. These reviews frequently identify knowledge gaps attributable to the observations that the most used laboratory mouse strains do not replicate key disease traits (e.g., granuloma necrosis) of human pulmonary TB [18-genetically controlled responses of epithelial and endothelial cells, neutrophils, and monocytes, macrophages to M. tuberculosis bacilli are the primary drivers of susceptibility to M. tuberculosis and to disease progression in pulmonary TB.…”

Section: Introductionmentioning

confidence: 99%

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Systems genetics uncover new loci containing functional gene candidates inMycobacterium tuberculosis-infected Diversity Outbred mice

Gatti,

Tyler,

Mahoney

et al. 2023

Preprint

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Mycobacterium tuberculosis,the bacillus that causes tuberculosis (TB), infects 2 billion people across the globe, and results in 8-9 million new TB cases and 1-1.5 million deaths each year. Most patients have no known genetic basis that predisposes them to disease. We investigated the complex genetic basis of pulmonary TB by modelling human genetic diversity with the Diversity Outbred mouse population. When infected withM. tuberculosis, one-third develop early onset, rapidly progressive, necrotizing granulomas and succumb within 60 days. The remaining develop non-necrotizing granulomas and survive longer than 60 days. Genetic mapping using clinical indicators of disease, granuloma histopathological features, and immune response traits identified five new loci on mouse chromosomes 1, 2, 4, 16 and three previously identified loci on chromosomes 3 and 17. Quantitative trait loci (QTLs) on chromosomes 1, 16, and 17, associated with multiple correlated traits and had similar patterns of allele effects, suggesting these QTLs contain important genetic regulators of responses toM. tuberculosis. To narrow the list of candidate genes in QTLs, we used a machine learning strategy that integrated gene expression signatures from lungs ofM. tuberculosis-infected Diversity Outbred mice with gene interaction networks, generating functional scores. The scores were then used to rank candidates for each mapped trait in each locus, resulting in 11 candidates:Ncf2, Fam20b, S100a8, S100a9, Itgb5, Fstl1, Zbtb20, Ddr1, Ier3, Vegfa,andZfp318. Importantly, all 11 candidates have roles in infection, inflammation, cell migration, extracellular matrix remodeling, or intracellular signaling. Further, all candidates contain single nucleotide polymorphisms (SNPs), and some but not all SNPs were predicted to have deleterious consequences on protein functions. Multiple methods were used for validation including (i) a statistical method that showed Diversity Outbred mice carrying PWH/PhJ alleles on chromosome 17 QTL have shorter survival; (ii) quantification of S100A8 protein levels, confirming predicted allele effects; and (iii) infection of C57BL/6 mice deficient for theS100a8gene. Overall, this work demonstrates that systems genetics using Diversity Outbred mice can identify new (and known) QTLs and new functionally relevant gene candidates that may be major regulators of granuloma necrosis and acute inflammation in pulmonary TB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systems genetics uncover new loci containing functional gene candidates inMycobacterium tuberculosis-infected Diversity Outbred mice

Gatti,

Tyler,

Mahoney

et al. 2023

Preprint

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“…For almost all infectious agents, the clinical manifestations of infection are highly variable, ranging from silent infection to lethal disease ( 25 ). The field of human genetics of infectious diseases aims to characterize the genetic variants accounting for this considerable interindividual variability.…”

Section: Human Genetics Of Infectious Diseasesmentioning

confidence: 99%

Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants

Cobat

Zhang

Effort

et al. 2023

Annu. Rev. Biomed. Data Sci.

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SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is silent or benign in most infected individuals, but causes hypoxemic COVID-19 pneumonia in about 10% of cases. We review studies of the human genetics of life-threatening COVID-19 pneumonia, focusing on both rare and common variants. Large-scale genome-wide association studies have identified more than 20 common loci robustly associated with COVID-19 pneumonia with modest effect sizes, some implicating genes expressed in the lungs or leukocytes. The most robust association, on chromosome 3, concerns a haplotype inherited from Neanderthals. Sequencing studies focusing on rare variants with a strong effect have been particularly successful, identifying inborn errors of type I interferon (IFN) immunity in 1–5% of unvaccinated patients with critical pneumonia, and their autoimmune phenocopy, autoantibodies against type I IFN, in another 15–20% of cases. Our growing understanding of the impact of human genetic variation on immunity to SARS-CoV-2 is enabling health systems to improve protection for individuals and populations. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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“…Genome-wide association studies (GWASs) are a powerful method to identify common genetic variants associated with risk, resistance, or other quantitative measures of infectious disease. 1 However, connecting variants identified by whole-organism GWAS to disease pathogenesis is often challenging—especially when it is unclear how the identified variants affect nearby genes or how these genes relate to the disease under investigation. To solve this, studies look among the disease-linked variants for those that associate with expression of nearby genes (called expression quantitative trait loci [eQTLs]), which can provide important clues, especially during stimulation with pathogens 2 or pathogen-associated molecular patterns.…”

Section: Introductionmentioning

confidence: 99%