scholarly journals Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms

2020 ◽  
pp. annrheumdis-2020-218481 ◽  
Author(s):  
Elena López-Isac ◽  
Samantha L Smith ◽  
Miranda C Marion ◽  
Abigail Wood ◽  
Marc Sudman ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Fine Mapping ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Enrichment Analysis ◽  
Joint Analysis ◽  
Integrative Approach ◽  
Nucleotide Polymorphisms ◽  
A Genome

ObjectivesJuvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit.MethodsWe performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes.ResultsOur analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology and IL6ST as a potential drug target.ConclusionsIn a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies.

scholarly journals Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study

2018 ◽  
Vol 109 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Dylan M Williams ◽  
Sara Hägg ◽  
Nancy L Pedersen
Keyword(s):  
Alzheimer Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Late Onset ◽  
Association Studies ◽  
Nucleotide Polymorphisms ◽  
Primary Methods ◽  
A Genome ◽  
Β Carotene

ABSTRACT Background Higher circulating antioxidant concentrations are associated with a lower risk of late-onset Alzheimer disease (AD) in observational studies, suggesting that diet-sourced antioxidants may be modifiable targets for reducing disease risk. However, observational evidence is prone to substantial biases that limit causal inference, including residual confounding and reverse causation. Objectives In order to infer whether long-term circulating antioxidant exposure plays a role in AD etiology, we tested the hypothesis that AD risk would be lower in individuals with lifelong, genetically predicted increases in concentrations of 4 circulating antioxidants that are modifiable by diet. Methods Two-sample Mendelian randomization analyses were conducted. First, published genetic association studies were used to identify single-nucleotide polymorphisms (SNPs) that determine variation in circulating ascorbate (vitamin C), β-carotene, retinol (vitamin A), and urate. Second, for each set of SNP data, statistics for genotype associations with AD risk were extracted from data of a genome-wide association study of late-onset AD cases and controls (n = 17,008 and 37,154, respectively). Ratio-of-coefficients and inverse-variance-weighted meta-analyses were the primary methods used to assess the 4 sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates. Results The models suggested that genetically determined differences in circulating ascorbate, retinol, and urate are not associated with differences in AD risk. All estimates were close to the null, with all ORs for AD ≥1 per unit increase in antioxidant exposure (ranging from 1.00 for ascorbate to 1.05 for retinol). There was little evidence to imply that pleiotropy had biased results. Conclusions Our findings suggest that higher exposure to ascorbate, β-carotene, retinol, or urate does not lower the risk of AD. Replication Mendelian randomization studies could assess this further, providing larger AD case-control samples and, ideally, using additional variants to instrument each exposure.

scholarly journals Genetic and metabolic signatures of Salmonella enterica subsp. enterica associated with animal sources at the pangenomic scale

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Meryl Vila Nova ◽  
Kévin Durimel ◽  
Kévin La ◽  
Arnaud Felten ◽  
Philippe Bessières ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Genome Wide Association Study ◽  
Enrichment Analysis ◽  
Public Health Issue ◽  
Nucleotide Polymorphisms ◽  
Genomic Signatures ◽  
Accessory Genes ◽  
European Nucleotide Archive ◽  
A Genome ◽  
Metabolic Signatures

Abstract Background Salmonella enterica subsp. enterica is a public health issue related to food safety, and its adaptation to animal sources remains poorly described at the pangenome scale. Firstly, serovars presenting potential mono- and multi-animal sources were selected from a curated and synthetized subset of Enterobase. The corresponding sequencing reads were downloaded from the European Nucleotide Archive (ENA) providing a balanced dataset of 440 Salmonella genomes in terms of serovars and sources (i). Secondly, the coregenome variants and accessory genes were detected (ii). Thirdly, single nucleotide polymorphisms and small insertions/deletions from the coregenome, as well as the accessory genes were associated to animal sources based on a microbial Genome Wide Association Study (GWAS) integrating an advanced correction of the population structure (iii). Lastly, a Gene Ontology Enrichment Analysis (GOEA) was applied to emphasize metabolic pathways mainly impacted by the pangenomic mutations associated to animal sources (iv). Results Based on a genome dataset including Salmonella serovars from mono- and multi-animal sources (i), 19,130 accessory genes and 178,351 coregenome variants were identified (ii). Among these pangenomic mutations, 52 genomic signatures (iii) and 9 over-enriched metabolic signatures (iv) were associated to avian, bovine, swine and fish sources by GWAS and GOEA, respectively. Conclusions Our results suggest that the genetic and metabolic determinants of Salmonella adaptation to animal sources may have been driven by the natural feeding environment of the animal, distinct livestock diets modified by human, environmental stimuli, physiological properties of the animal itself, and work habits for health protection of livestock.

EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Ischemic Stroke ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Visceral Adiposity ◽  
Large Artery ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5×10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48×10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01×10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16×10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

scholarly journals An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Misbah Razzaq ◽  
Maria Jesus Iglesias ◽  
Manal Ibrahim-Kosta ◽  
Louisa Goumidi ◽  
Omar Soukarieh ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Genome Wide Association Study ◽  
Susceptibility Gene ◽  
Biological Traits ◽  
Nucleotide Polymorphisms ◽  
Ann Model ◽  
Neural Network Approach ◽  
A Genome ◽  
Increased Risk ◽  
Artificial Neural

AbstractVenous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10–7) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

scholarly journals Genome-Wide Association Study (GWAS) for Examining the Genomics Controlling Prickle Production in Red Raspberry (Rubus idaeus L.)

Agronomy ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 27
Author(s):  
Archana Khadgi ◽  
Courtney A. Weber
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genomic Region ◽  
Rubus Idaeus ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Red Raspberry ◽  
Genome Wide ◽  
A Genome ◽  
Genotype By Sequencing

Red raspberry (Rubus idaeus L.) is an expanding high-value berry crop worldwide. The presence of prickles, outgrowths of epidermal tissues lacking vasculature, on the canes, petioles, and undersides of leaves complicates both field management and harvest. The utilization of cultivars with fewer prickles or prickle-free canes simplifies production. A previously generated population segregating for prickles utilizing the s locus between the prickle-free cultivar Joan J (ss) and the prickled cultivar Caroline (Ss) was analyzed to identify the genomic region associated with prickle development in red raspberry. Genotype by sequencing (GBS) was combined with a genome-wide association study (GWAS) using fixed and random model circulating probability unification (FarmCPU) to analyze 8474 single nucleotide polymorphisms (SNPs) and identify significant markers associated with the prickle-free trait. A total of four SNPs were identified on chromosome 4 that were associated with the phenotype and were located near or in annotated genes. This study demonstrates how association genetics can be used to decipher the genetic control of important horticultural traits in Rubus, and provides valuable information about the genomic region and potential genes underlying the prickle-free trait.

scholarly journals Genome-Wide Association Analysis of Growth Curve Parameters in Chinese Simmental Beef Cattle

Animals ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 192
Author(s):  
Xinghai Duan ◽  
Bingxing An ◽  
Lili Du ◽  
Tianpeng Chang ◽  
Mang Liang ◽  
...  
Keyword(s):  
Beef Cattle ◽  
Candidate Genes ◽  
Growth Curve ◽  
Growth And Development ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Coefficient Of Determination ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

The objective of the present study was to perform a genome-wide association study (GWAS) for growth curve parameters using nonlinear models that fit original weight–age records. In this study, data from 808 Chinese Simmental beef cattle that were weighed at 0, 6, 12, and 18 months of age were used to fit the growth curve. The Gompertz model showed the highest coefficient of determination (R2 = 0.954). The parameters’ mature body weight (A), time-scale parameter (b), and maturity rate (K) were treated as phenotypes for single-trait GWAS and multi-trait GWAS. In total, 9, 49, and 7 significant SNPs associated with A, b, and K were identified by single-trait GWAS; 22 significant single nucleotide polymorphisms (SNPs) were identified by multi-trait GWAS. Among them, we observed several candidate genes, including PLIN3, KCNS3, TMCO1, PRKAG3, ANGPTL2, IGF-1, SHISA9, and STK3, which were previously reported to associate with growth and development. Further research for these candidate genes may be useful for exploring the full genetic architecture underlying growth and development traits in livestock.

scholarly journals Identifying Personalized Metabolic Signatures in Breast Cancer

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 20
Author(s):  
Priyanka Baloni ◽  
Wikum Dinalankara ◽  
John C. Earls ◽  
Theo A. Knijnenburg ◽  
Donald Geman ◽  
...  
Keyword(s):  
Drug Targets ◽  
Metabolic Networks ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Estrogen Metabolism ◽  
Acid Oxidation ◽  
A Genome ◽  
Context Specific

Cancer cells are adept at reprogramming energy metabolism, and the precise manifestation of this metabolic reprogramming exhibits heterogeneity across individuals (and from cell to cell). In this study, we analyzed the metabolic differences between interpersonal heterogeneous cancer phenotypes. We used divergence analysis on gene expression data of 1156 breast normal and tumor samples from The Cancer Genome Atlas (TCGA) and integrated this information with a genome-scale reconstruction of human metabolism to generate personalized, context-specific metabolic networks. Using this approach, we classified the samples into four distinct groups based on their metabolic profiles. Enrichment analysis of the subsystems indicated that amino acid metabolism, fatty acid oxidation, citric acid cycle, androgen and estrogen metabolism, and reactive oxygen species (ROS) detoxification distinguished these four groups. Additionally, we developed a workflow to identify potential drugs that can selectively target genes associated with the reactions of interest. MG-132 (a proteasome inhibitor) and OSU-03012 (a celecoxib derivative) were the top-ranking drugs identified from our analysis and known to have anti-tumor activity. Our approach has the potential to provide mechanistic insights into cancer-specific metabolic dependencies, ultimately enabling the identification of potential drug targets for each patient independently, contributing to a rational personalized medicine approach.

scholarly journals Haplotype- and SNP-Based GWAS for Growth and Wood Quality Traits in Eucalyptus cladocalyx Trees under Arid Conditions

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 148
Author(s):  
Camilo E. Valenzuela ◽  
Paulina Ballesta ◽  
Sunny Ahmar ◽  
Sajid Fiaz ◽  
Parviz Heidari ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Wood Quality ◽  
Tree Height ◽  
Mediterranean Ecosystems ◽  
Primary Metabolism ◽  
Arid Environments ◽  
Nucleotide Polymorphisms ◽  
Haplotype Blocks ◽  
A Genome ◽  
Stem Straightness

The agricultural and forestry productivity of Mediterranean ecosystems is strongly threatened by the adverse effects of climate change, including an increase in severe droughts and changes in rainfall distribution. In the present study, we performed a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNPs) and haplotype blocks associated with the growth and wood quality of Eucalyptus cladocalyx, a tree species suitable for low-rainfall sites. The study was conducted in a progeny-provenance trial established in an arid site with Mediterranean patterns located in the southern Atacama Desert, Chile. A total of 87 SNPs and 3 haplotype blocks were significantly associated with the 6 traits under study (tree height, diameter at breast height, slenderness coefficient, first bifurcation height, stem straightness, and pilodyn penetration). In addition, 11 loci were identified as pleiotropic through Bayesian multivariate regression and were mainly associated with wood hardness, height, and diameter. In general, the GWAS revealed associations with genes related to primary metabolism and biosynthesis of cell wall components. Additionally, associations coinciding with stress response genes, such as GEM-related 5 and prohibitin-3, were detected. The findings of this study provide valuable information regarding genetic control of morphological traits related to adaptation to arid environments.

Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2709-2712 ◽  
Author(s):  
Maria E. Sarasquete ◽  
Ramon García-Sanz ◽  
Luis Marín ◽  
Miguel Alcoceba ◽  
Maria C. Chillón ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cytochrome P450 ◽  
Genome Wide Association Study ◽  
Osteonecrosis Of The Jaw ◽  
Bisphosphonate Therapy ◽  
Polymorphism Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
A Genome

Abstract We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P = 1.07 × 10−6, P = 4.231 × 10−6, P = 6.22 × 10−6, and P = 2.15 × 10−6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).

scholarly journals Global Analysis of the Genetic Variations in miRNA-Targeted Sites and Their Correlations With Agronomic Traits in Rapeseed

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengfei Xu ◽  
Yantao Zhu ◽  
Yanfeng Zhang ◽  
Jianxia Jiang ◽  
Liyong Yang ◽  
...  
Keyword(s):  
Mirna Target ◽  
Target Genes ◽  
Rare Variants ◽  
Agronomic Traits ◽  
Global Analysis ◽  
Variant Calling ◽  
Genetic Variations ◽  
Nucleotide Polymorphisms ◽  
A Genome ◽  
Target Sites

MicroRNAs (miRNAs) and their target genes play vital roles in crops. However, the genetic variations in miRNA-targeted sites that affect miRNA cleavage efficiency and their correlations with agronomic traits in crops remain unexplored. On the basis of a genome-wide DNA re-sequencing of 210 elite rapeseed (Brassica napus) accessions, we identified the single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELs) in miRNA-targeted sites complementary to miRNAs. Variant calling revealed 7.14 million SNPs and 2.89 million INDELs throughout the genomes of 210 rapeseed accessions. Furthermore, we detected 330 SNPs and 79 INDELs in 357 miRNA target sites, of which 33.50% were rare variants. We also analyzed the correlation between the genetic variations in miRNA target sites and 12 rapeseed agronomic traits. Eleven SNPs in miRNA target sites were significantly correlated with phenotypes in three consecutive years. More specifically, three correlated SNPs within the miRNA-binding regions of BnSPL9-3, BnSPL13-2, and BnCUC1-2 were in the loci associated with the branch angle, seed weight, and silique number, respectively; expression profiling suggested that the variation at these 3 miRNA target sites significantly affected the expression level of the corresponding target genes. Taken together, the results of this study provide researchers and breeders with a global view of the genetic variations in miRNA-targeted sites in rapeseed and reveal the potential effects of these genetic variations on elite agronomic traits.

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