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Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia in Females: the DEFINE-FMD study

ABSTRACT: Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia in Females: the DEFINE-FMD study

PROVIDER: PRJNA1014393 | ENA |

REPOSITORIES: ENA

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Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia in Females: the DEFINE-FMD study

Project description:Fibromuscular dysplasia (FMD) is a poorly understood but relatively common vascular disease affecting 3-5% of adult females. The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm which can lead to hypertension, stroke, heart attack and even death. While a limited number of gene variants have been associated with FMD, there are no animal models and few insights as to why this disease occurs. By integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE-FMD study, we inferred 18 gene co-expression networks, four of which were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this gene co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation; a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. Using linkage disequilibrium score regression to determine the genetic contribution to disease, we found that this supernetwork accounts for a significant proportion of FMD heritability (H squared). These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue to address this challenging disease.

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Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia in Females: the DEFINE-FMD study

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Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia in Females: the DEFINE-FMD study

Project description:Fibromuscular dysplasia (FMD) is poorly understood but relatively common vascular disease affecting 3-5% of adult females. 1-3 The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm which can lead to hypertension, stroke, heart attack and even death. 3-7 While a limited number of gene variants have been associated with FMD,8-12 there are no animal models and few insights as to why this disease occurs. 3,13 By integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE-FMD study, we inferred 18 gene co-expression networks, of which four were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this gene co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation/aneurysm; a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. Using linkage disequilibrium score regression to determine genetic contribution to disease, 14-16 we found that this supernetwork accounts for 45.4% of FMD heritability (H2 ). These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue to address this challenging disease.

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Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia

Project description:Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia

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Project description:We performed miRNA and mRNA profiling at postnatal day 14 and day 29 to compare hyperoxia-induced bronchopulmonary dysplasia and wild type. We built potential miRNA-mRNA interaction networks specific to brochopulmonary dysplasia. Replicated time course of mouse lung development at 2 time points (P14, P29). Three replicates per time point for bronchopulmonary dysplasia induced by hyperoxia mouse lung, and two replicates per time point for wild type mouse lung. This dataset represents the mRNA expression profiling component of the study.

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