The contribution of non-coding regulatory elements to cardiovascular disease

Villar, Diego; Frost, Stephanie; Deloukas, Panos; Tinker, Andrew

doi:10.1098/rsob.200088

Cited by 22 publications

(18 citation statements)

References 148 publications

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“…Indeed, although genes involved in many biological pathways such as vascular tone and remodelling, lipid metabolism and inflammation have been identified, the precise molecular mechanism is still unknown 182,183 . Coronary artery diseases and myocardial infarction were the first diseases targeted in GWAS studies 184 . A study by Huang revealed the association between 3′‐UTR mutations of MEF2A and coronary artery diseases.…”

Section: Non‐coding Variants In Coronary Artery Diseases and Strokesmentioning

confidence: 99%

Role of non‐coding variants in cardiovascular disease

Heshmatzad,

Naderi,

Maleki

et al. 2023

J Cellular Molecular Medi

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Cardiovascular diseases (CVDs) are the leading cause of death and account for 31% of mortality, worldwide. 1 Some progressive pathologies linked to cardiovascular diseases are familial hypercholesterolemia, different types of cardiomyopathies, thoracic/aortic aneurysms, congenital heart diseases, coronary artery diseases, heart failure 2 and strokes. 3,4 Despite the promising results of conventional pharmacological treatments, cardiovascular diseases still have poor prognoses. 5 Many factors are associated with cardiovascular disease pathogenesis. Among them, the genetic component is a beneficial tool for the risk stratification of cardiovascular disease development.Improvements in sequencing technologies have conferred not only better clinical management and diagnosis of genetic disorders but also a better understanding of genetic disorders with unknown mechanisms. 6 Before the completion of the Human Genome Project, genes associated with rare Mendelian forms of cardiovascular diseases had been identified. Recent years have found the identification of

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Section: Non‐coding Variants In Coronary Artery Diseases and Strokesmentioning

confidence: 99%

Role of non‐coding variants in cardiovascular disease

Heshmatzad,

Naderi,

Maleki

et al. 2023

J Cellular Molecular Medi

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“…19,20 or deep intronic regions. 21 Our understanding of the consequences of these types of variants and the non-coding genome organization in general is more limited than for exonic variants, but it is steadily expanding for example by continued mapping and functional characterization of regulatory elements, 22,23 expanded analysis of regulatory variants, [24][25][26] and improvements to prediction tools to aid in their interpretation are under development. [27][28][29]…”

Section: Initial Attempts For Prenatal Utilization Of Whole Genome Se...mentioning

confidence: 99%

Emerging technologies for prenatal diagnosis: The application of whole genome and RNA sequencing

Liu

Vossaert

2022

Prenatal Diagnosis

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DNA sequencing technologies for clinical genetic testing have been rapidly evolving in recent years, and steadily become more important within the field of prenatal diagnostics. This review aims to give an overview of recent developments and to describe how they have the potential to fill the gaps of the currently clinically implemented methods for prenatal diagnosis of various genetic disorders. It has been shown for postnatal testing that whole genome sequencing provides a set of added benefits compared to exome sequencing, and it is to be expected that this will be the case for prenatal testing as well. RNA‐sequencing, already used postnatally, can provide valuable complementary data to DNA‐based testing, and aid in variant interpretation. While not ready for clinical implementation, emerging technologies such as long‐read and Hi‐C sequencing analyses might add to the toolbox for interpreting the expanding genetic data sets generated by genome‐wide sequencing. Lastly, we also discuss some more practical implications of introducing these emerging technologies, which generate larger and larger genomic data sets, in the prenatal field.

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“…Coronary Artery Disease (CAD) is a type of cardio-vascular disease associated with thickening of arterial walls and is a major cause of disease in developed countries (Malakar et al, 2019). Recent GWAS of CAD has shown a significant portion of associated SNPs to lie in non-coding regions of the DNA (Selvarajan et al, 2021;Villar et al, 2020). Using L-Hi-C-Reg we mapped a total of 193 SNPs (141 GWAS and 52 in LD) of total 409 SNPs to 1036 genes across the 55 cell lines with a total of 1737 interactions (Figure 6A, Table 1).…”

Section: Identifying Downstream Pathways Impacted By Regulatory Variantsmentioning

confidence: 99%

Leveraging epigenomes and three-dimensional genome organization for interpreting regulatory variation

Baur

Schreiber

Shin

et al. 2021

Preprint

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Understanding the impact of regulatory variants on complex phenotypes is a significant challenge because the genes and pathways that are targeted by such variants are typically unknown. Furthermore, a regulatory variant might influence a particular gene's expression in a cell type or tissue-specific manner. Cell-type specific long-range regulatory interactions that occur between a distal regulatory sequence and a gene offers a powerful framework for understanding the impact of regulatory variants on complex phenotypes. However, high-resolution maps of such long-range interactions are available only for a handful of model cell lines. To address this challenge, we have developed L-HiC-Reg, a Random Forests based regression method to predict high-resolution contact counts in new cell lines, and a network-based framework to identify candidate cell line-specific gene networks targeted by a set of variants from a Genome-wide association study (GWAS). We applied our approach to predict interactions in 55 Roadmap Epigenome Consortium cell lines, which we used to interpret regulatory SNPs in the NHGRI GWAS catalogue. Using our approach, we performed an in-depth characterization of fifteen different phenotypes including Schizophrenia, Coronary Artery Disease (CAD) and Crohn's disease. In CAD, we found differentially wired subnetworks consisting of known as well as novel gene targets of regulatory SNPs. Taken together, our compendium of interactions and associated network-based analysis pipeline offers a powerful resource to leverage long-range regulatory interactions to examine the context-specific impact of regulatory variation in complex phenotypes.

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The contribution of non-coding regulatory elements to cardiovascular disease

Cited by 22 publications

References 148 publications

Role of non‐coding variants in cardiovascular disease

Role of non‐coding variants in cardiovascular disease

Emerging technologies for prenatal diagnosis: The application of whole genome and RNA sequencing

Leveraging epigenomes and three-dimensional genome organization for interpreting regulatory variation

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