Integrative analysis of bulk and single-cell RNA-seq data for cardiometabolic disease

心脏代谢疾病的批量和单细胞 RNA-seq 数据的综合分析

• 批准号: 10448317
• 负责人: Mingyao Li
• 金额: $ 12.19万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448317
• 关键词: Abdomen; Accounting; Adipocytes; Adipose tissue; Allelic Imbalance; Architecture; Atherosclerosis; Body mass index; Buffers; Candidate Disease Gene; Cardiometabolic Disease; Catalogs; Cells; Cholesterol; Complex; Computer software; Data; Data Analyses; Data Set; Disease; Elements; Endothelial Cells; Etiology; Fibroblasts; Foundations; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genome; Genotype; Heterogeneity; High-Throughput RNA Sequencing; Human; Immune; Knowledge; Link; Lipids; Location; Loose connective tissue; Measurable; Metabolic; Methods; Molecular; Morbidity - disease rate; Muscle; Myocardial Infarction; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Needle biopsy procedure; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peripheral; Precision therapeutics; Publishing; Quantitative Trait Loci; Regulatory Element; Reporting; Resolution; Risk; Role; Sampling; Single Nucleotide Polymorphism; Statistical Data Interpretation; Statistical Methods; Stroke; System; Testing; Tissues; Triglycerides; Untranslated RNA; Variant; Waist-Hip Ratio; Whole Blood; adiponectin; base; cardiometabolic risk; cell type; energy balance; genetic association; genetic variant; genome wide association study; genomic locus; human data; insight; interest; lifestyle factors; macrophage; mortality; novel; open source; single-cell RNA sequencing; statistics; stem cells; subcutaneous; therapeutic target; trait; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Cardiometabolic diseases (CMD), including obesity, type 2 diabetes, heart attack, stroke, and atherosclerosis, are caused by the effects and complex interplay of genetic and lifestyle factors. In the past decade, there has been a dramatic increase of CMD, which represents important causes of morbidity and mortality worldwide. Therefore, there is a great interest to understand the etiology and pathophysiology of CMD. Recent genome- wide association studies (GWAS) have provided increased insight into the genetic basis for CMD and related traits. Although GWAS have identified strong and highly replicated association of genetic loci for CMD and their related traits, GWAS findings can only suggest locations of associated variants and not directly link any one gene within a region to disease. Since most GWAS-identified single nucleotide polymorphisms (SNPs) are located in non-coding regions of the genome, their influence on disease is likely to be on modulating RNA expression by acting as expression quantitative trait loci (eQTL). Excess adipose tissue, especially in central abdominal depots, is associated with increased risk of CMD. Subcutaneous adipose tissue stores additional lipids and acts as a buffering system for lipid energy balance, thus providing a protective role for CMD. Previous eQTL studies in subcutaneous adipose tissue have implicated genes involved in obesity and metabolic traits. However, the role of candidate genes identified in GWAS is still not yet clear because published eQTL studies were based on bulk tissue gene expression in adipose. Adipose tissue is a loose connective tissue that is composed mostly of adipocytes. In addition to adipocytes, adipose tissue also contains adipocyte progenitor cells, endothelial cells, fibroblasts, and various immune cells such as macrophages. The resulting heterogeneity between samples can confound the analysis of bulk tissue data. To overcome these limitations, we propose to perform integrative secondary data analysis of publically available bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) data from human adipose. We will test the hypothesis that measurable molecular deficits that include cell types and gene expression occur in adipose for CMD. We will further integrate with publically available GWAS data on CMD to advance post-GWAS interpretation of CMD genetic results. By detailed characterization of cell-type composition and cell-type- specific gene expression changes in human adipose, our results will elucidate the functional roles of GWAS findings that are still poorly understood and can power precision therapeutic targeting of CMD.

项目总结

项目成果

High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis.

人颈动脉粥样硬化的高维单细胞多模态景观。

• DOI: 10.1101/2023.07.13.23292633
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Bashore,AlexanderC;Yan,Hanying;Xue,Chenyi;Zhu,LucieY;Kim,Eunyoung;Mawson,Thomas;Coronel,Johana;Chung,Allen;Ho,Sebastian;Ross,LeilaS;Kissner,Michael;Passegué,Emmanuelle;Bauer,RobertC;Maegdefessel,Lars;Li,Mingyao;Reilly,Mu
• 通讯作者: Reilly,Mu