scholarly journals Cell-specific chromatin landscape of human coronary artery resolves regulatory mechanisms of disease risk

2021 ◽  
Author(s):  
Adam W. Turner ◽  
Sheng'en Hu ◽  
Jose Verdezoto Mosquera ◽  
Wei Feng Ma ◽  
Chani Hodonsky ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Coronary Artery ◽  
Single Cell ◽  
Dna Sequences ◽  
Association Studies ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Cad Risk

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across several cell types. Genome-wide association studies (GWAS) have identified over 170 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements (CREs). Here, we applied single-cell ATAC-seq to profile 28,316 cells across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell type-specific elements, transcription factors, and prioritized functional CAD risk variants via quantitative trait locus and sequence-based predictive modeling. We identified a number of candidate mechanisms for smooth muscle cell transition states and identified putative binding sites for risk variants. We further employed DNA element to gene linkage to nominate disease-associated key driver transcription factors such as PRDM16 and TBX2. This single cell atlas provides a critical step towards interpreting cis-regulatory mechanisms in the vessel wall across the continuum of CAD risk.

scholarly journals High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways

2019 ◽  
Vol 12 (3) ◽  
Author(s):  
Örjan Åkerborg ◽  
Rapolas Spalinskas ◽  
Sailendra Pradhananga ◽  
Anandashankar Anil ◽  
Pontus Höjer ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
High Resolution ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Expression Levels ◽  
Risk Variants ◽  
Genome Wide ◽  
Artery Disease

Background: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease. Methods: In this study, we generated high-resolution genomic interaction maps (≈750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac. Results: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated. Conclusions: In summary, we present a catalog of candidate genes regulated by coronary artery disease–related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

scholarly journals Fine mapping with epigenetic information and 3D structure

2022 ◽  
Author(s):  
Gisela Orozco
Keyword(s):  
Complex Traits ◽  
Drug Targets ◽  
Association Studies ◽  
3D Structure ◽  
Improve Patient Care ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Functional Interpretation ◽  
Risk Variants ◽  
Increase Risk

AbstractSince 2005, thousands of genome-wide association studies (GWAS) have been published, identifying hundreds of thousands of genetic variants that increase risk of complex traits such as autoimmune diseases. This wealth of data has the potential to improve patient care, through personalized medicine and the identification of novel drug targets. However, the potential of GWAS for clinical translation has not been fully achieved yet, due to the fact that the functional interpretation of risk variants and the identification of causal variants and genes are challenging. The past decade has seen the development of great advances that are facilitating the overcoming of these limitations, by utilizing a plethora of genomics and epigenomics tools to map and characterize regulatory elements and chromatin interactions, which can be used to fine map GWAS loci, and advance our understanding of the biological mechanisms that cause disease.

scholarly journals Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

2019 ◽  
Author(s):  
Sara R. Rashkin ◽  
Rebecca E. Graff ◽  
Linda Kachuri ◽  
Khanh K. Thai ◽  
Stacey E. Alexeeff ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Large Population ◽  
Regulatory Elements ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Pan Cancer ◽  
Shared Genetic

AbstractDeciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

scholarly journals Cis-epistasis at the LPA locus and risk of coronary artery disease

2019 ◽  
Author(s):  
Lingyao Zeng ◽  
Nazanin Mirza-Schreiber ◽  
Claudia Lamina ◽  
Stefan Coassin ◽  
Christopher P. Nelson ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Studies ◽  
Arterial Disease ◽  
Genome Wide Association Studies ◽  
Interaction Patterns ◽  
Cardiovascular Risks ◽  
Increased Risk ◽  
Artery Disease ◽  
Cad Risk

AbstractIdentification of epistasis affecting complex human traits has been challenging. Focusing on known coronary artery disease (CAD) risk loci, we explore pairwise statistical interactions between 8,068 SNPs from ten CAD genome-wide association studies (n=30,180). We discovered rs1800769 and rs9458001 in the vicinity of the LPA locus to interact in modulating CAD risk (P=1.75×10−13). Specific genotypes (e.g., rs1800769 CT) displayed either significantly decreased or increased risk for CAD in the context of genotypes of the respective other SNP (e.g., rs9458001 GG vs. AA). In the UK Biobank (n=450,112) significant interaction of this SNP pair was replicated for CAD (P=3.09×10−22), and was also found for aortic valve stenosis (P=6.95×10−7) and peripheral arterial disease (P=2.32×10−4). Identical interaction patterns affected circulating lipoprotein(a) (n=5,953; P=8.7×10−32) and hepatic apolipoprotein(a) (apo(a)) expression (n=522, P=2.6×10−11). We further interrogated potential biological implications of the variants and propose a mechanism explaining epistasis that ultimately may translate to substantial cardiovascular risks.

scholarly journals Genetic Risk of Coronary Artery Disease, Features of Atherosclerosis, and Coronary Plaque Burden

2020 ◽  
Vol 9 (3) ◽  
Author(s):  
Morten Krogh Christiansen ◽  
Louise Nissen ◽  
Simon Winther ◽  
Peter Loof Møller ◽  
Lars Frost ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Coronary Artery Calcium Score ◽  
Association Studies ◽  
Calcium Score ◽  
Plaque Burden ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Stenosis Severity ◽  
Artery Disease

Background Polygenic risk scores ( PRS s) based on risk variants from genome‐wide association studies predict coronary artery disease ( CAD ) risk. However, it is unknown whether the PRS is associated with specific CAD characteristics. Methods and Results We consecutively included 1645 patients with suspected stable CAD undergoing coronary computed tomography angiography. A multilocus PRS was calculated as the weighted sum of CAD risk variants. Plaques were evaluated using an 18‐segment model and characterized by stenosis severity and composition (soft [0%‐19% calcified], mixed‐soft [20%‐49% calcified], mixed‐calcified [50%‐79% calcified], or calcified [≥80% calcified]). Coronary artery calcium score and segment stenosis score were used to characterize plaque burden. For each standard deviation increase in the PRS , coronary artery calcium score increased by 78% ( P =4.1e‐26) and segment stenosis score increased by 16% ( P =2.4e‐29) in the fully adjusted model. The PRS was associated with a higher prevalence of obstructive plaques (odds ratio [ OR ] : 1.78, P =5.6e‐16), calcified ( OR : 1.69, P =6.5e‐17), mixed‐calcified ( OR : 1.67, P =7.3e‐9), mixed‐soft ( OR : 1.45, P =1.6e‐6), and soft plaques ( OR : 1.49, P =2.5e‐6), and a higher prevalence of plaque in each coronary vessel (all P <1.0e‐4). However, when analyzing data on a plaque level (3007 segments with plaque in 849 patients) the PRS was not associated with stenosis severity, plaque composition, or localization (all P >0.05). Conclusions Our results suggest that polygenic risk based on large genome‐wide association studies increases CAD risk through an increased burden of coronary atherosclerosis rather than promoting specific plaque features. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02264717.

scholarly journals Insights into Gene Regulatory Networks in Chondrocytes

2019 ◽  
Vol 20 (24) ◽  
pp. 6324 ◽  
Author(s):  
Hironori Hojo ◽  
Shinsuke Ohba
Keyword(s):  
Transcription Factors ◽  
Dna Sequences ◽  
Regulatory Networks ◽  
Developmental Process ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Gene Expressions ◽  
A Genome ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

Chondrogenesis is a key developmental process that molds the framework of our body and generates the skeletal tissues by coupling with osteogenesis. The developmental processes are well-coordinated by spatiotemporal gene expressions, which are hardwired with gene regulatory elements. Those elements exist as thousands of modules of DNA sequences on the genome. Transcription factors function as key regulatory proteins by binding to regulatory elements and recruiting cofactors. Over the past 30 years, extensive attempts have been made to identify gene regulatory mechanisms in chondrogenesis, mainly through biochemical approaches and genetics. More recently, newly developed next-generation sequencers (NGS) have identified thousands of gene regulatory elements on a genome scale, and provided novel insights into the multiple layers of gene regulatory mechanisms, including the modes of actions of transcription factors, post-translational histone modifications, chromatin accessibility, the concept of pioneer factors, and three-dimensional chromatin architecture. In this review, we summarize the studies that have improved our understanding of the gene regulatory mechanisms in chondrogenesis, from the historical studies to the more recent works using NGS. Finally, we consider the future perspectives, including efforts to improve our understanding of the gene regulatory landscape in chondrogenesis and potential applications to the treatment of chondrocyte-related diseases.

scholarly journals System Genetics Including Causal Inference Identify Immune Targets for Coronary Artery Disease and the Lifespan

2021 ◽  
Author(s):  
Valentin Bon-Baret ◽  
Arnaud Chignon ◽  
Marie-Chloé Boulanger ◽  
Zhonglin Li ◽  
Deborah Argaud ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Immune Response ◽  
Coronary Artery ◽  
Single Cell ◽  
Randomized Clinical Trials ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Artery Disease ◽  
Cell Expression ◽  
The Impact

Background - Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference. Methods - Herein, we implemented a system genetics approach to identify causally associated immune targets implicated in atheroma. We leveraged genome-wide association studies to perform mapping and Mendelian Randomization (MR) to assess causal associations between gene expression in blood cells with CAD and the lifespan. Expressed genes (eGenes) were prioritized in network and in single-cell expression derived from plaque immune cells. Results - Among 840 CAD-associated blood eGenes, 37 were predicted causally associated with CAD and 6 were also associated with the parental lifespan in MR. In multivariable MR, the impact of eGenes on the lifespan potential was mediated by the CAD risk. Predicted causal eGenes were central in network. FLT1 and CCR5 were identified as targets of approved drugs, whereas 22 eGenes were deemed tractable for the development of small molecules and/or antibodies. Analyses of plaque immune single-cell expression identified predicted causal eGenes enriched in macrophages ( GPX1 , C4orf3 ) and involved in ligand receptor interactions ( CCR5 ). Conclusions - We identified 37 blood eGenes predicted causally associated with CAD. The predicted expression for 6 eGenes impacted the lifespan potential through the risk of CAD. Prioritization based on network, annotations and single cell expression identified targets deemed tractable for the development of drugs and for drug repurposing.

scholarly journals Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

2020 ◽  
Author(s):  
M. Ryan Corces ◽  
Anna Shcherbina ◽  
Soumya Kundu ◽  
Michael J. Gloudemans ◽  
Laure Frésard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Association Studies ◽  
Regulatory Elements ◽  
Brain Regions ◽  
Chromatin Accessibility ◽  
Adult Brain ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms

ABSTRACTGenome-wide association studies (GWAS) have identified thousands of variants associated with disease phenotypes. However, the majority of these variants do not alter coding sequences, making it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the adult human brain through profiling of the chromatin accessibility landscapes and three-dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to integrate this multi-omic framework and predict dozens of functional single nucleotide polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for Alzheimer’s disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia and MAL in oligodendrocytes for Parkinson’s disease (PD). Moreover, we dissect the complex inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene contacts in neurons that increase MAPT expression and may mediate this disease association. This work greatly expands our understanding of inherited variation in AD and PD and provides a roadmap for the epigenomic dissection of noncoding regulatory variation in disease.

scholarly journals Genetic regulatory mechanisms of smooth muscle cells map to coronary artery disease risk loci

2018 ◽  
Author(s):  
Boxiang Liu ◽  
Milos Pjanic ◽  
Ting Wang ◽  
Trieu Nguyen ◽  
Michael Gloudemans ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Regulatory Mechanisms ◽  
Human Populations ◽  
Genome Wide Association Studies ◽  
Artery Disease ◽  
Cad Risk

AbstractCoronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWAS) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMC) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMC. We assessed the relevance of HCASMC to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that modulate CAD risk through HCASMC, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMC, while other annotated genes may have multiple cell and tissue targets. Together, these results provide new tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.

scholarly journals Beyond association: successes and challenges in linking non-coding genetic variation to functional consequences that modulate Alzheimer’s disease risk

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Gloriia Novikova ◽  
Shea J. Andrews ◽  
Alan E. Renton ◽  
Edoardo Marcora
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Association Studies ◽  
Regulatory Elements ◽  
Causal Variant ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Risk Variants ◽  
Cellular Phenotypes

AbstractAlzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide; however, no disease-modifying treatments are currently available. Genome-wide association studies (GWASs) have identified more than 40 loci associated with AD risk. However, most of the disease-associated variants reside in non-coding regions of the genome, making it difficult to elucidate how they affect disease susceptibility. Nonetheless, identification of the regulatory elements, genes, pathways and cell type/tissue(s) impacted by these variants to modulate AD risk is critical to our understanding of disease pathogenesis and ability to develop effective therapeutics. In this review, we provide an overview of the methods and approaches used in the field to identify the functional effects of AD risk variants in the causal path to disease risk modification as well as describe the most recent findings. We first discuss efforts in cell type/tissue prioritization followed by recent progress in candidate causal variant and gene nomination. We discuss statistical methods for fine-mapping as well as approaches that integrate multiple levels of evidence, such as epigenomic and transcriptomic data, to identify causal variants and risk mechanisms of AD-associated loci. Additionally, we discuss experimental approaches and data resources that will be needed to validate and further elucidate the effects of these variants and genes on biological pathways, cellular phenotypes and disease risk. Finally, we discuss future steps that need to be taken to ensure that AD GWAS functional mapping efforts lead to novel findings and bring us closer to finding effective treatments for this devastating disease.

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