scholarly journals Panton-Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial genome-wide association study

2018 ◽  
Author(s):  
Bernadette C Young ◽  
Sarah G Earle ◽  
Sona Soeng ◽  
Poda Sar ◽  
Varun Kumar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Bacterial Genome ◽  
Strong Relationship ◽  
Genome Wide Association ◽  
Tropical Regions ◽  
Genome Wide ◽  
A Genome

AbstractPyomyositis is a severe bacterial infection of skeletal muscle, commonly affecting children in tropical regions and predominantly caused by Staphylococcus aureus. To understand the contribution of bacterial genomic factors to pyomyositis, we conducted a genome-wide association study of S. aureus cultured from 101 children with pyomyositis and 417 children with asymptomatic nasal carriage attending the Angkor Hospital for Children in Cambodia. We found a strong relationship between bacterial genetic variation and pyomyositis, with estimated heritability 63.8% (95% CI 49.2-78.4%). The presence of the Panton-Valentine leucocidin (PVL) locus increased the odds of pyomyositis 130-fold (p =10-17.9). The signal of association mapped both to the PVL-coding sequence and the sequence immediately upstream. Together these regions explained > 99.9% of heritability. Our results establish staphylococcal pyomyositis, like tetanus and diphtheria, as critically dependent on expression of a single toxin and demonstrate the potential for association studies to identify specific bacterial genes promoting severe human disease.

scholarly journals Panton–Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial GWAS

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Bernadette C Young ◽  
Sarah G Earle ◽  
Sona Soeng ◽  
Poda Sar ◽  
Varun Kumar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Strong Relationship ◽  
Nasal Carriage ◽  
Tropical Regions ◽  
Genome Wide ◽  
A Genome ◽  
Bacterial Genetic ◽  
Bacterial Genes

Pyomyositis is a severe bacterial infection of skeletal muscle, commonly affecting children in tropical regions, predominantly caused by Staphylococcus aureus. To understand the contribution of bacterial genomic factors to pyomyositis, we conducted a genome-wide association study of S. aureus cultured from 101 children with pyomyositis and 417 children with asymptomatic nasal carriage attending the Angkor Hospital for Children, Cambodia. We found a strong relationship between bacterial genetic variation and pyomyositis, with estimated heritability 63.8% (95% CI 49.2–78.4%). The presence of the Panton–Valentine leucocidin (PVL) locus increased the odds of pyomyositis 130-fold (p=10-17.9). The signal of association mapped both to the PVL-coding sequence and to the sequence immediately upstream. Together these regions explained over 99.9% of heritability (95% CI 93.5–100%). Our results establish staphylococcal pyomyositis, like tetanus and diphtheria, as critically dependent on a single toxin and demonstrate the potential for association studies to identify specific bacterial genes promoting severe human disease.

scholarly journals Bacterial Genome wide association studies (bGWAS) and transcriptomics identifies cryptic antimicrobial resistance mechanisms in Acinetobacter baumannii

2019 ◽  
Author(s):  
Chandler Roe ◽  
Charles H.D. Williamson ◽  
Adam J. Vazquez ◽  
Kristen Kyger ◽  
Michael Valentine ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Acinetobacter Baumannii ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Bacterial Genome ◽  
Genome Wide Association ◽  
Multiple Drug ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

AbstractAntimicrobial resistance (AMR) in the nosocomial pathogen, Acinetobacter baumannii, is becoming a serious public health threat. While some mechanisms of AMR have been reported, understanding novel mechanisms of resistance is critical for identifying emerging resistance. One of the first steps in identifying novel AMR mechanisms is performing genotype/phenotype association studies. However, performing genotype/phenotype association studies is complicated by the plastic nature of the A. baumannii pan-genome. In this study, we compared the antibiograms of 12 antimicrobials associated with multiple drug families for 84 A. baumannii isolates, many isolated in Arizona, USA. in silico screening of these genomes for known AMR mechanisms failed to identify clear correlations for most drugs. We then performed a genome wide association study (GWAS) looking for associations between all possible 21-mers; this approach generally failed to identify mechanisms that explained the resistance phenotype. In order to decrease the genomic noise associated with population stratification, we compared four phylogenetically-related pairs of isolates with differing susceptibility profiles. RNA-Sequencing (RNA-Seq) was performed on paired isolates and differentially expressed genes were identified. In these isolate pairs, we identified four different potential mechanisms, highlighting the difficulty of broad AMR surveillance in this species. To verify and validate differential expression, amplicon sequencing was performed. These results suggest that a diagnostic platform based on gene expression rather than genomics alone may be beneficial in certain surveillance efforts. The implementation of such advanced diagnostics coupled with increased AMR surveillance will potentially improve A. baumannii infection treatment and patient outcomes.

scholarly journals Genome-Wide Association Study Dissects Resistance Loci against Bacterial Blight in a Diverse Rice Panel from the 3000 Rice Genomes Project

Rice ◽  
2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jialing Lu ◽  
Chunchao Wang ◽  
Dan Zeng ◽  
Jianmin Li ◽  
Xiaorong Shi ◽  
...  
Keyword(s):  
Association Study ◽  
Bacterial Blight ◽  
Genome Wide Association Study ◽  
Linear Regression Analysis ◽  
Specific Interaction ◽  
Genome Wide Association ◽  
Lesion Length ◽  
Tropical Regions ◽  
Genome Wide ◽  
A Genome

Abstract Background Bacterial blight (BB), caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most devastating bacterial diseases of rice in temperate and tropical regions. Breeding and deployment of resistant cultivars carrying major resistance (R) genes has been the most effective approach for BB management. However, because of specific interaction of each R gene with the product of the corresponding pathogen avirulence or effector gene, new pathogen strains that can overcome the deployed resistance often emerge rapidly. To deal with ever-evolving Xoo, it is necessary to identify novel R genes and resistance quantitative trait loci (QTL). Results BB resistance of a diverse panel of 340 accessions from the 3000 Rice Genomes Project (3 K RGP) was evaluated by artificial inoculation with four representative Xoo strains, namely Z173 (C4), GD1358 (C5), V from China and PXO339 (P9a) from Philippines. Using the 3 K RG 4.8mio filtered SNP Dataset, a total of 11 QTL associated with BB resistance on chromosomes 4, 5, 11 and 12 were identified through a genome-wide association study (GWAS). Among them, eight resistance loci, which were narrowed down to relatively small genomic intervals, coincided with previously reported QTL or R genes, e.g. xa5, xa25, xa44(t). The other three QTL were putative novel loci associated with BB resistance. Linear regression analysis showed a dependence of BB lesion length on the number of favorable alleles, suggesting that pyramiding QTL using marker-assisted selection would be an effective approach for improving resistance. In addition, the Hap2 allele of LOC_Os11g46250 underlying qC5–11.1 was validated as positively regulating resistance against strain C5. Conclusions Our findings provide valuable information for the genetic improvement of BB resistance and application of germplasm resources in rice breeding programs.

scholarly journals GENOME-WIDE ASSOCIATION STUDY OF EXTREME HUMAN LONGEVITY DISCOVERS UNCOMMON LONGEVITY VARIANTS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S209-S209
Author(s):  
Anastasia Gurinovich ◽  
Anastasia Gurinovich ◽  
Zeyuan Song ◽  
Stacy L Andersen ◽  
Thomas T Perls ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Human Longevity ◽  
Mixed Effect ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Abstract The strong heritability of extreme human longevity supports the hypothesis that this is a genetically-regulated trait. However, association studies focused on common genetic variants have discovered a limited number of longevity-associated genes. We conducted a genome-wide association study of 4,216 individuals including 1317 centenarians from the New England Centenarian Study (median age = 104 years) using >9M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The set included approximately 5M uncommon variants. The associations were tested using a mixed effect logistic regression model with genotype-based kinship covariance of the random effects to adjust for cryptic relations using the package GENESIS. The analysis discovered 45 genome-wide significant SNPs (p< 5E-08) including 8 new loci in chromosomes 3, 6, 7, 9, 10, 14 and 15 in addition to the APOE locus. The list includes new pQTLs in serum that suggest a new biological mechanism involved in extreme human longevity.

scholarly journals Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

2022 ◽  
Author(s):  
Richard J Packer ◽  
Nick Shrine ◽  
Robert Hall ◽  
Carl Melbourne ◽  
Rebecca Thompson ◽  
...  
Keyword(s):  
Association Study ◽  
Respiratory Disease ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Chromosome 11 ◽  
Genome Wide ◽  
Sputum Production ◽  
A Genome ◽  
Wide Range

Background Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. Methods We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (P<5x10-8) were fine-mapped and putative causal genes identified by gene expression analysis. GWAS of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease amongst the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWAS). Findings From a GWAS of 9,714 cases and 48,471 controls, we identified six novel genome-wide significant signals for chronic sputum production including the Human Leukocyte Antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and the FUT2 locus. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino-acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations. Interpretation Novel signals at the FUT2 and mucin loci highlight mucin flucosylation as a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

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