Integrative analysis of bulk and single-cell RNA-seq data from human retina for age-related macular degeneration

项目摘要 视网膜相关性黄斑变性（AMD）影响着超过1000万美国人，是受影响人数的两倍。 阿尔茨海默病和等于所有癌症患者的总和。AMD是全球第三大 视力丧失的原因虽然有短期疗法可用于一种类型的AMD，但潜在的治疗方法是有效的。 这种疾病是无法治愈的，并且视力丧失是许多个体的最终结果。虽然进步 在视网膜疾病诊断方面进展迅速，针对原发性遗传病的AMD的特异性治疗， 或代谢缺陷由于缺乏对疾病途径的了解而进展缓慢。缓慢 进展是多种因素的结果，包括缺乏关于参与启动的细胞类型的信息。 AMD.因此，迫切需要了解哪些细胞对AMD的发展有贡献 病理对人AMD中发生的细胞和基因表达变化的鉴定将促进AMD的治疗。 设计纳入受影响细胞类型的动物和体外细胞模型，用于未来的药物开发。 虽然全基因组关联研究（GWAS）已经确定了强和高度重复的关联， 对于AMD的遗传位点，GWAS的发现只能表明相关变异的位置，而不能直接将任何 一个区域内的一个基因对疾病的影响。由于大多数GWAS鉴定的单核苷酸多态性位于 在非编码区中，它们对疾病的影响被认为是通过充当 表达数量性状基因座。在这个项目中，我们建议进行综合二级数据分析， 可从以下公司获得的批量RNA测序（RNA-seq）和单细胞RNA-seq（scRNA-seq）数据： 死后的人视网膜，以测试这一假设，可测量的分子缺陷，包括细胞类型和 基因表达发生在AMD眼睛的视网膜中。我们将进一步与可用的GWAS数据集成 以推进对AMD遗传结果的GWAS后解释。通过详细描述细胞类型 组成和细胞类型特异性基因表达的变化，我们的研究结果将阐明 GWAS发现的功能作用仍然知之甚少，可以为精确的治疗靶向提供动力 关于AMD所有新的计算工具都将作为用户友好的开源软件发布。的可视化和 我们亦会设立查询网站，方便市民公布调查结果。

PROJECT SUMMARY Age-related macular degeneration (AMD) affects over 10 million Americans, twice the number affected by Alzheimer disease and equal to the total of all cancer patients combined. Worldwide, AMD is the third largest cause of vision loss. While there are short-term therapies available for one type of AMD, the underlying disease is by no means cured, and vision loss is an eventual outcome for many individuals. Although advances in retinal disease diagnostics have progressed rapidly, specific treatments for AMD directed at primary genetic or metabolic defects have progressed slowly due to a lack of understanding of the disease pathway. The slow progress is a result of multiple factors including lack of information about cell types involved in the initiation of AMD. Therefore, there is an urgent need to understand what cells are contributing to the development of AMD pathology. Identification of the cellular and gene expression changes occurring in human AMD will facilitate the design of animal and in vitro cell models incorporating the affected cell types for future drug development. While genome-wide association studies (GWAS) have identified strong and highly replicated association of genetic loci for AMD, 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 are located in non-coding regions, their influence on disease is believed to be on modulating RNA expression by acting as expression quantitative trait loci. In this project, 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 postmortem human retina, to test the hypothesis that measurable molecular deficits that include cell types and gene expression occur in the retina of AMD eyes. We will further integrate with publically available GWAS data on AMD to advance post-GWAS interpretation of AMD genetic results. By detailed characterization of cell type composition and cell type-specific gene expression changes in human eye, our results will elucidate the functional roles of GWAS findings that are still poorly understood and can power precision therapeutic targeting of AMD. All new computational tools will be released as user-friendly open source software. A visualization and query website will also be created to facilitate dissemination of our findings.