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 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

Abstract Adolescent 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 Human library of cardiac promoters and enhancers

2020 ◽  
Author(s):  
Ruslan M. Deviatiiarov ◽  
Anna Gams ◽  
Roman Syunyaev ◽  
Tatiana V. Tatarinova ◽  
Oleg Gusev ◽  
...  
Keyword(s):  
Heart Diseases ◽  
Association Studies ◽  
Expression Patterns ◽  
Critical Role ◽  
Regulatory Elements ◽  
Specific Cell ◽  
Genome Wide Association Studies ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Human Donor

AbstractGenome regulatory elements play a critical role during cardiac development and maintenance of normal physiological homeostasis, and genome-wide association studies identified a large number of SNPs associated with cardiovascular diseases localized in intergenic zones. We used cap analysis of gene expression (CAGE) to identify transcription start sites (TSS) with one nucleotide resolution that effectively maps genome regulatory elements in a representative collection of human heart tissues. Here we present a comprehensive and fully annotated CAGE atlas of human promoters and enhancers from four chambers of the non-diseased human donor hearts, including both atria and ventricles. We have identified 10,528 novel regulatory elements, where 2,750 are classified as TSS and 4,258 novel enhancers, which were validated with ChIP-seq libraries and motif enrichment analysis. We found that heart-region specific expression patterns are primarily based on the alternative promoter and specific enhancer activity. Our study significantly increased evidence of the association of regulatory elements-located variants with heart morphology and pathologies. The precise location of cardiac disease-related SNPs within the regulatory regions and their correlation with a specific cell type offers a new understanding of genetic heart diseases.

scholarly journals Human atlas of cardiac promoters and enhancers reveals important role of regulatory elements in heritable diseases

2020 ◽  
Author(s):  
Ruslan Deviatiiarov ◽  
Anna Gams ◽  
Roman Syunyaev ◽  
Tatiana Tatarinova ◽  
Oleg Gusev ◽  
...  
Keyword(s):  
Heart Diseases ◽  
Association Studies ◽  
Expression Patterns ◽  
Critical Role ◽  
Regulatory Elements ◽  
Specific Cell ◽  
Genome Wide Association Studies ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Human Donor

Abstract Genome regulatory elements play a critical role during cardiac development and maintenance of normal physiological homeostasis, and genome-wide association studies identified a large number of SNPs associated with cardiovascular diseases localized in intergenic zones. We used cap analysis of gene expression (CAGE) to identify transcription start sites (TSS) with one nucleotide resolution that effectively maps genome regulatory elements in a representative collection of human heart tissues. Here we present a comprehensive and fully annotated CAGE atlas of human promoters and enhancers from four chambers of the non-diseased human donor hearts, including both atria and ventricles. We have identified 10,528 novel regulatory elements, where 2,750 are classified as TSS and 4,258 novel enhancers, which were validated with ChIP-seq libraries and motif enrichment analysis. We found that heart-region specific expression patterns are primarily based on the alternative promoter and specific enhancer activity. Our study significantly increased evidence of the association of regulatory elements-located variants with heart morphology and pathologies. The precise location of cardiac disease-related SNPs within the regulatory regions and their correlation with a specific cell type offers a new understanding of genetic heart diseases.

scholarly journals Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

2011 ◽  
Vol 20 (7) ◽  
pp. 1456-1466 ◽  
Author(s):  
Swarkar Sharma ◽  
Xiaochong Gao ◽  
Douglas Londono ◽  
Shonn E. Devroy ◽  
Kristen N. Mauldin ◽  
...  
Keyword(s):  
Adolescent Idiopathic Scoliosis ◽  
Idiopathic Scoliosis ◽  
Association Studies ◽  
Susceptibility Genes ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

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 Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis

2020 ◽  
Vol 79 (11) ◽  
pp. 1438-1445
Author(s):  
Young-Chang Kwon ◽  
Jiwoo Lim ◽  
So-Young Bang ◽  
Eunji Ha ◽  
Mi Yeong Hwang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Large Fraction ◽  
Genome Wide Association ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Bioinformatics Analyses ◽  
Specific Expression ◽  
Genome Wide

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta<5×10−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

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.

Adolescent Idiopathic Scoliosis – Future Molecular-Based Diagnostic and Prognostic Testing

2019 ◽  
Vol 21 (4) ◽  
pp. 253-260
Author(s):  
Radoslav Zamborský ◽  
Boris Liščák ◽  
Martin Trepáč ◽  
Andrey Švec ◽  
Ľuboš Danisovič
Keyword(s):  
Adolescent Idiopathic Scoliosis ◽  
Idiopathic Scoliosis ◽  
Association Studies ◽  
Three Dimensional ◽  
Reliability And Validity ◽  
Genome Project ◽  
Genome Wide Association Studies ◽  
Appropriate Treatment ◽  
Surgical Treatments ◽  
The Human Genome Project

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spine mainly affecting the younger population. Earlier detection of the disorder leads to appropriate treatment and better outcomes, thus avoiding highly invasive surgical treatments. The currently available tests for the disease identification have lost their reliability and validity with time. In the past few decades, efforts have been directed towards developing a highly reliable prognostic test for AIS. Towards this end, several strategies have been employed including biochemical, biomechanical and gene-based tests. Among the three, the gene-based technology has received much attention in recent past. Notably, this is due to the fact that the human genome project, followed by genome-wide association studies (GWAS), facilitated the identification of candidate genes for disorders like AIS. Several promising biomarker genes have been identified. However, their global validations were disappointing as these genes were shown to be limited to a particular group of people/ethnicities. Such observations limit the development of a reliable global molecular/biochemical test for AIS. The currently used AIS ScoliScoreTM also has several limitations. With continued disappointments in the identification of biomarkers for AIS and lack of appropriate tests, researchers have diverted their efforts towards several alternative avenues. A ray of hope is emerging from recent observations on the association of non-coding microRNAs and epigenetic factors that might arise as future reliable markers for AIS, thus paving the way for appropriate clinical management of this disorder.

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