scholarly journals Antipsychotic-induced epigenomic reorganization in frontal cortex samples from individuals with schizophrenia

2021 ◽  
Author(s):  
Bohan Zhu ◽  
Richard I Ainsworth ◽  
Zengmiao Wang ◽  
Salvador Sierra ◽  
Chengyu Deng ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Histone Modifications ◽  
Association Studies ◽  
Regulatory Elements ◽  
Postmortem Brain ◽  
Antipsychotic Treatment ◽  
Genome Wide Association Studies ◽  
Epigenetic Marks ◽  
Genome Wide ◽  
The Impact

Genome wide association studies have revealed >150 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, no study so far has profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects or the effect of antipsychotic treatment on such epigenetic marks. Here we show the first comprehensive epigenomic characterization of the frontal cortex of 29 individuals with schizophrenia and 29 matched controls, including histone modifications associated with active promoters and enhancers H3K4me3 and H3K27ac along with RNA expression in neuronal and glial nuclei. Schizophrenia subjects exhibited thousands of cell type-specific epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, RGS4 and HTR2A. Comparing untreated and treated schizophrenia subjects with controls, our findings provide entirely new insights into differentially modified genes associated with unexpected pathways that are potential markers of antipsychotic treatment. Additionally, we show that the effect of age on the epigenomic landscape is more pronounced in frontal cortex samples of antipsychotic-treated schizophrenia subjects. Together, our data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark the impact of age and antipsychotic treatment on chromatin organization.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

scholarly journals Genomic basis of striking fin shapes and colours in the fighting fish

2021 ◽  
Author(s):  
Le Wang ◽  
Fei Sun ◽  
Zi Yi Wan ◽  
Baoqing Ye ◽  
Yanfei Wen ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Association Studies ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Major Effect ◽  
Betta Splendens ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Phenotypic Variations ◽  
Genomic Basis

Abstract Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole genome sequencing, QTL mapping, genome-wide association studies and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double tail mutant was suggested to be caused by a deletion in a zic1/zic4 co-enhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.

scholarly journals Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

2020 ◽  
Author(s):  
Katherina C. Chua ◽  
Chenling Xiong ◽  
Carol Ho ◽  
Taisei Mushiroda ◽  
Chen Jiang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Elements ◽  
Hazard Ratio ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Sensory Peripheral Neuropathy ◽  
Genome Wide ◽  
Microtubule Targeting Agents

AbstractMicrotubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

scholarly journals Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

2020 ◽  
Author(s):  
Nadja Makki ◽  
Jingjing Zhao ◽  
Zhaoyang Liu ◽  
Walter L. Eckalbar ◽  
Aki Ushiki ◽  
...  
Keyword(s):  
Adolescent Idiopathic Scoliosis ◽  
Connective Tissue ◽  
Idiopathic Scoliosis ◽  
Association Studies ◽  
Regulatory Elements ◽  
Intervertebral Discs ◽  
Genome Wide Association Studies ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Genome Wide

AbstractAdolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ∼3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

scholarly journals Addressing the Missing Heritability Problem With the Help of Regulatory Features

2019 ◽  
Vol 15 ◽  
pp. 117693431986086
Author(s):  
Shan-Shan Dong ◽  
Yan Guo ◽  
Tie-Lin Yang
Keyword(s):  
Target Genes ◽  
Association Studies ◽  
Complex Diseases ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Missing Heritability ◽  
Genome Wide ◽  
Missing Heritability Problem

Genome-wide association studies (GWASs) have successfully identified thousands of susceptibility loci for human complex diseases. However, missing heritability is still a challenging problem. Considering most GWAS loci are located in regulatory elements, we recently developed a pipeline named functional disease-associated single-nucleotide polymorphisms (SNPs) prediction (FDSP), to predict novel susceptibility loci for complex diseases based on the interpretation of regulatory features and published GWAS results with machine learning. When applied to type 2 diabetes and hypertension, the predicted susceptibility loci by FDSP were proved to be capable of explaining additional heritability. In addition, potential target genes of the predicted positive SNPs were significantly enriched in disease-related pathways. Our results suggested that taking regulatory features into consideration might be a useful way to address the missing heritability problem. We hope FDSP could offer help for the identification of novel susceptibility loci for complex diseases.

scholarly journals The Impact of Improved Microarray Coverage and Larger Sample Sizes on Future Genome-Wide Association Studies

2013 ◽  
Vol 37 (4) ◽  
pp. 383-392 ◽  
Author(s):  
Karla J. Lindquist ◽  
Eric Jorgenson ◽  
Thomas J. Hoffmann ◽  
John S. Witte
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Sample Sizes ◽  
Genome Wide ◽  
The Impact ◽  
Larger Sample

scholarly journals Anaerobic conditions unmask antimicrobial resistance

2021 ◽  
Author(s):  
Ashton Creasy-Marrazzo ◽  
Morteza M. Saber ◽  
Manasi Kamat ◽  
Laura S. Bailey ◽  
Firdausi Qadri ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Association Studies ◽  
Anaerobic Respiration ◽  
Anaerobic Growth ◽  
Genome Wide Association Studies ◽  
Anaerobic Conditions ◽  
Aerobic Conditions ◽  
Minimal Inhibitory Concentrations ◽  
Genome Wide ◽  
The Impact

Antimicrobial resistance (AMR) in Gram negative enteropathogens is an urgent threat to the antibiotic formulary. These taxa undergo anaerobic respiration within the host, yet little is known about how anaerobic conditions influence antimicrobial resistance (AMR). The facultative enteropathogen Vibrio cholerae was chosen as a model to determine the impact of anaerobic growth on AMR because cholera is one of the few non-invasive diarrhoeal diseases for which antibiotics are indicated, albeit conditionally. V. cholerae isolates from a single outbreak were tested for resistance by minimal inhibitory concentrations (MIC) under aerobic and anaerobic conditions against clinically relevant antibiotics. Here we show that the odds of classifying isolates as resistant under anaerobic compared to aerobic conditions increased over 20 times for ciprofloxacin and 50 times for azithromycin, yet for doxycycline, all isolates remained below the breakpoint for resistance. Genome-wide association studies (GWAS) found significant associations between known and unknown genetic elements and AMR phenotypes that varied by oxygen exposure and antibiotic concentrations. In most cases, AMR phenotypes were more heritable, and more genes significantly associated with AMR were discovered, under anaerobic conditions compared to aerobic conditions. These findings challenge the paradigm of testing facultative enteropathogens for AMR under aerobic conditions alone. This experimental approach establishes a new, more sensitive framework to track and investigate mechanisms of AMR.

scholarly journals Proportion of idiopathic pulmonary fibrosis risk explained by known genetic loci

2020 ◽  
Author(s):  
Olivia C Leavy ◽  
Shwu-Fan Ma ◽  
Philip L Molyneaux ◽  
Toby M Maher ◽  
Justin M Oldham ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genetic Architecture ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Risk Variants ◽  
Genome Wide ◽  
The Impact ◽  
Insight Into

Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

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