scholarly journals Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 701
Author(s):  
Yuying Fan ◽  
Yue Wang ◽  
Gregory A. Korfanty ◽  
Meagan Archer ◽  
Jianping Xu
Keyword(s):  
Aspergillus Fumigatus ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Clinical Importance ◽  
Genome Wide Association ◽  
Missense Mutations ◽  
Genome Wide ◽  
Resistant Strains ◽  
The Common

Aspergillus fumigatus is a ubiquitous fungus and the main agent of aspergillosis, a common fungal infection in the immunocompromised population. Triazoles such as itraconazole and voriconazole are the common first-line drugs for treating aspergillosis. However, triazole resistance in A. fumigatus has been reported in an increasing number of countries. While most studies of triazole resistance have focused on mutations in the triazole target gene cyp51A, >70% of triazole-resistant strains in certain populations showed no mutations in cyp51A. To identify potential non-cyp51A mutations associated with triazole resistance in A. fumigatus, we analyzed the whole genome sequences and triazole susceptibilities of 195 strains from 12 countries. These strains belonged to three distinct clades. Our genome-wide association study (GWAS) identified a total of six missense mutations significantly associated with itraconazole resistance and 18 missense mutations with voriconazole resistance. In addition, to investigate itraconazole and pan-azole resistance, Fisher’s exact tests revealed 26 additional missense variants tightly linked to the top 20 SNPs obtained by GWAS, of which two were consistently associated with triazole resistance. The large number of novel mutations related to triazole resistance should help further investigations into their molecular mechanisms, their clinical importance, and the development of a comprehensive molecular diagnosis toolbox for triazole resistance in A. fumigatus.

scholarly journals Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena R. R. Wells ◽  
Fatin N. Zainul Abidin ◽  
Maxim B. Freidin ◽  
Frances M. K. Williams ◽  
Sally J. Dawson
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Significance Threshold ◽  
Genome Wide ◽  
Final Sample ◽  
Close Proximity ◽  
Repressor Complex

AbstractTinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E−06.

scholarly journals Genome-Wide Association Study of H/L Traits in Chicken

Animals ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 260 ◽  
Author(s):  
Bo Zhu ◽  
Qinghe Li ◽  
Ranran Liu ◽  
Maiqing Zheng ◽  
Jie Wen ◽  
...  
Keyword(s):  
Disease Resistance ◽  
Association Study ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Gene Annotation ◽  
Immune Defense ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

Presently, the heterophil-to-lymphocyte (H/L) ratio is being studied extensively as a disease resistance trait. Through intricate mechanisms to identify and destroy pathogenic microorganisms, heterophils play a pivotal role in the immune defense systems of avian species. To reveal the genetic basis and molecular mechanisms affecting the H/L ratio, phenotypic and H/L data from 1650 white feather chicken broilers were used in performing a genome-wide association study. A self-developed, chicken-specific 55K chip was used for heterophils, lymphocytes, and H/L classification, according to individual genomic DNA profiles. We identified five significant single nucleotide polymorphisms (SNPs) when the genome-wide significance threshold was set to 5% (p < 2.42 × 10−6). A total of 15 SNPs obtained seemingly significant levels (p < 4.84 × 10−5). Gene annotation indicated that CARD11 (Caspase recruitment domain family member 11), BRIX1 (Biogenesis of ribosomes BRX1), and BANP (BTG3 associated nuclear protein) play a role in H/L-associated cell regulation and potentially constitute candidate gene regions for cellular functions dependent on H/L ratios. These results lay the foundation for revealing the genetic basis of disease resistance and future marker-assisted selection for disease resistance.

Periodontitis Risk Variants at SIGLEC5 Impair ERG and MAFB Binding

2021 ◽  
pp. 002203452110499
Author(s):  
R. Mueller ◽  
A. Chopra ◽  
H. Dommisch ◽  
A.S. Schaefer
Keyword(s):  
Association Study ◽  
Target Gene ◽  
Genome Wide Association Study ◽  
Biological Effects ◽  
Regulatory Elements ◽  
Genome Wide Association ◽  
Luciferase Reporter ◽  
Genome Wide ◽  
A Genome ◽  
Allele Specific

Periodontitis is a common complex inflammatory disease of the oral cavity. It is characterized by inflammation of gingival tissues and alveolar bone loss. Recently, a genome-wide association study and 2 genome-wide association study meta-analyses found 2 associated regions (haplotype blocks) at the inhibitory immune receptor gene SIGLEC5 to increase the risk for periodontitis. The aims of the current study were the identification of the putative causal variants underlying these associations, characterization of their molecular biological effects, and validation of SIGLEC5 as the target gene. We mapped the associated single-nucleotide polymorphisms to DNA elements with predictive features of regulatory functions and screened the associated alleles for transcription factor (TF) binding sites. Antibody electrophoretic mobility shift assays (EMSAs) with allele-specific probes were used to identify TF binding and to quantify allele-specific effects on binding affinities. Luciferase reporter assays were used to quantify the effect directions and allele-specific strength of the associated regulatory elements. We used CRISPR-dCas9 gene activation to validate SIGLEC5 as a target of the association. EMSA in peripheral blood mononuclear cells showed that E-26 transformation–specific TF-related gene (ERG) binds at rs11084095, with almost complete loss of binding at the minor A-allele. Allele-specific reporter genes showed enhancer function of the DNA sequence at rs11084095, which was abrogated in the background of the A-allele. EMSA in B lymphocytes showed that TF MAF bZIP (MAFB) binds at the common G-allele of rs4284742, whereas the minor A-allele reduced TF binding by 69%, corresponding to 9-fold reduction of luciferase reporter gene activity by the A-allele. Using CRISPR-dCas9, we showed that the enhancer at rs4284742 strongly activated SIGLEC5 expression, validating this gene as the target gene of the association. We conclude that rs11084095 and rs4284742 are putatively causal for the genome-wide significant associations with periodontitis at SIGLEC5 that impair ERG and MAFB binding, respectively.

scholarly journals Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

2019 ◽  
Vol 78 (10) ◽  
pp. 1430-1437 ◽  
Author(s):  
Yusuke Kawamura ◽  
Hirofumi Nakaoka ◽  
Akiyoshi Nakayama ◽  
Yukinori Okada ◽  
Ken Yamamoto ◽  
...  
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Serum Uric Acid Level ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Significance Level ◽  
Replication Studies ◽  
Genome Wide ◽  
First Time

ObjectiveThe first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.MethodsWe carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).ResultsThis new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10–8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.ConclusionsThis meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

scholarly journals Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

Gut ◽  
2017 ◽  
Vol 67 (10) ◽  
pp. 1855-1863 ◽  
Author(s):  
Jonas Rosendahl ◽  
Holger Kirsten ◽  
Eszter Hegyi ◽  
Peter Kovacs ◽  
Frank Ulrich Weiss ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Clinical Importance ◽  
Population Based ◽  
Genome Wide Association ◽  
Expression Ratio ◽  
Alcoholic Chronic Pancreatitis ◽  
Genome Wide ◽  
A Genome

ObjectiveAlcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.ResultsWe replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

scholarly journals Genome-wide association study (GWAS) reveals genetic loci of lead (Pb) tolerance during seedling establishment in rapeseed (Brassica napus L.)

2020 ◽  
Author(s):  
Fugui Zhang ◽  
Xin Xiao ◽  
Kun Xu ◽  
Xi Cheng ◽  
Ting Xie ◽  
...  
Keyword(s):  
Brassica Napus ◽  
Association Study ◽  
Seedling Establishment ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genetic Loci ◽  
Brassica Napus L ◽  
Pb Stress ◽  
Genome Wide

Abstract Background Lead (Pb) pollution in soil has become one of the major environmental threats to plant growth and human health. Safe utilization of Pb contaminated soil by phytoremediation require Pb tolerant rapeseed ( Brassica napus L.) accessions. However, breeding of new B. napus cultivars tolerance to Pb stress has been restricted by limited knowledge on molecular mechanisms involved in Pb tolerance. This work was carried out to identify genetic loci related to Pb tolerance during seedling establishment in rapeseed. Results Pb tolerance, which was assessed by quantifying radicle length (RL) under 0 or 100 mg/L Pb stress condition, shown an extensive variation in 472 worldwide-collected rapeseed accessions. Based on the criterion of relative RL>80%, six Pb tolerant genotypes were selected. Four quantitative trait loci (QTL) associated with Pb tolerance were identified by Genome-wide association study. The expression level of nine promising candidate genes, including GSTUs , BCATs , UBP13 , TBR and HIPP01 , located in these four QTL regions, were significantly higher or induced by Pb in Pb tolerant accessions in comparison to Pb sensitive accessions. Conclusion To our knowledge, this is the first study on Pb tolerant germplasms and genomic loci in B. napus . The findings can provide valuable genetic resources for the breeding of Pb tolerant B. napus cultivar and understanding of Pb tolerance mechanism in Brassica species.

scholarly journals Genome wide association study of plant height and tiller number in hulless barley

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260723
Author(s):  
Yixiong Bai ◽  
Xiaohong Zhao ◽  
Xiaohua Yao ◽  
Youhua Yao ◽  
Likun An ◽  
...  
Keyword(s):  
Association Study ◽  
Plant Height ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Tiller Number ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Hulless Barley ◽  
Genome Wide ◽  
A Genome

Hulless barley (Hordeum vulgare L. var. nudum), also called naked barley, is a unique variety of cultivated barley. The genome-wide specific length amplified fragment sequencing (SLAF-seq) method is a rapid deep sequencing technology that is used for the selection and identification of genetic loci or markers. In this study, we collected 300 hulless barley accessions and used the SLAF-seq method to identify candidate genes involved in plant height (PH) and tiller number (TN). We obtained a total of 1407 M paired-end reads, and 228,227 SLAF tags were developed. After filtering using an integrity threshold of >0.8 and a minor allele frequency of >0.05, 14,504,892 single-nucleotide polymorphisms (SNP) loci were screened out. The remaining SNPs were used for the construction of a neighbour-joining phylogenetic tree, and the three subcluster members showed no obvious differentiation among regional varieties. We used a genome wide association study approach to identify 1006 and 113 SNPs associated with TN and PH, respectively. Based on best linear unbiased predictors (BLUP), 41 and 29 SNPs associated with TN and PH, respectively. Thus, several of genes, including Hd3a and CKX5, may be useful candidates for the future genetic breeding of hulless barley. Taken together, our results provide insight into the molecular mechanisms controlling barley architecture, which is important for breeding and yield.

scholarly journals Temporal dynamics of QTL effects on vegetative growth in Arabidopsis thaliana

2020 ◽  
Author(s):  
Rhonda C. Meyer ◽  
Kathleen Weigelt-Fischer ◽  
Dominic Knoch ◽  
Marc Heuermann ◽  
Yusheng Zhao ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Association Study ◽  
Vegetative Growth ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Temporal Dynamics ◽  
Expression Patterns ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

ABSTRACTWe assessed early vegetative growth in a population of 382 accessions of Arabidopsis thaliana using automated non-invasive high-throughput phenotyping. All accessions were imaged daily from seven to 18 days after sowing in three independent experiments and genotyped using the Affymetrix 250k SNP array. Projected leaf area (PLA) was derived from image analysis and used to calculate relative growth rates (RGR). In addition, initial seed size was determined. The generated data sets were used jointly for a genome-wide association study that identified 238 marker-trait associations (MTAs) individually explaining up to 8 % of the total phenotypic variation. Co-localisation of MTAs occurred at 33 genomic positions. At 21 of these positions, sequential co-localisation of MTAs for two to nine consecutive days was observed. The detected MTAs for PLA and RGR could be grouped according to their temporal expression patterns, emphasising that temporal variation of MTA action can be observed even during the vegetative growth phase, a period of continuous formation and enlargement of seemingly similar rosette leaves. This indicates that causal genes may be differentially expressed in successive periods. Analyses of the temporal dynamics of biological processes are needed to gain important insight into the molecular mechanisms of growth-controlling processes in plants.HighlightA genome-wide association study including the factor time highlighted that early plant growth in Arabidopsis is governed by several medium and many small effect loci, most of which act only during short phases of two to nine days.

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