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

项目总结 心脏代谢疾病(CMD)，包括肥胖、2型糖尿病、心脏病发作、中风和动脉粥样硬化， 是由遗传和生活方式因素的影响和复杂的相互作用造成的。在过去的十年里，有 CMD急剧增加，这是世界范围内发病率和死亡率的重要原因。 因此，对CMD的病因和病理生理学有很大的兴趣。最新的基因组- 广泛的关联研究(GWAS)提供了对CMD及其相关基因基础的更多洞察力 特征。尽管Gwas已经确定了CMD及其相关基因座之间强烈且高度重复的关联 对于相关性状，GWAS的发现只能提示相关变异的位置，而不能直接与任何一个联系起来 一个区域内的基因对疾病有影响。由于大多数GWAS鉴定的单核苷酸多态(SNPs)是 它们位于基因组的非编码区，对疾病的影响很可能是对RNA的调节 作为表达的数量性状基因座(EQTL)。脂肪组织过多，特别是在中央 腹部发育不良与CMD的风险增加有关。皮下脂肪组织储存额外的 脂质，并作为脂质能量平衡的缓冲系统，从而为CMD提供保护作用。 此前对皮下脂肪组织的eQTL研究表明，与肥胖和肥胖有关的基因 新陈代谢特征。然而，在GWAS中确定的候选基因的作用仍然不清楚，因为 已发表的eQTL研究是基于脂肪中大量组织基因的表达。脂肪组织是疏松的 主要由脂肪细胞组成的结缔组织。除了脂肪细胞，脂肪组织还 含有脂肪细胞前体细胞、内皮细胞、成纤维细胞和各种免疫细胞，如 巨噬细胞。由此产生的样本之间的异质性可能会混淆对大量组织数据的分析。至 克服这些限制，我们建议对公众可获得的数据进行综合二次数据分析 来自人类脂肪的批量RNA测序(RNA-seq)和单细胞RNA-seq(scRNA-seq)数据。我们将测试 假设包括细胞类型和基因表达在内的可测量的分子缺陷发生在脂肪中 对于CMD。我们将进一步整合可公开获得的关于CMD的全球气候变化数据，以推进后全球气候变化 对CMD遗传结果的解释。通过对细胞类型组成和细胞类型的详细描述- 人类脂肪中特异性基因表达的变化，我们的结果将阐明GWAs的功能作用 这些发现仍然知之甚少，可以为CMD的精确治疗靶向提供动力。

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.