Variant to gene mapping for Alzheimer's Disease

阿尔茨海默病基因图谱变异

• 批准号: 10210343
• 负责人: Struan F A Grant
• 金额: $ 71.75万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210343
• 关键词: 3-Dimensional; Address; Affect; Age; Alleles; Alzheimer' s Disease; American; Amyloid beta-Protein; Biological Assay; Biological Markers; CRISPR interference; CRISPR screen; CRISPR/Cas technology; Cell model; Cells; Chromatin; Chromosome Mapping; Collaborations; Collection; Complex; Data; Disease; Early Endosome; Enhancers; Environmental Risk Factor; Epigenetic Process; Etiology; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genetic Diseases; Genetic Variation; Genomic Segment; Genomics; Human; Infrastructure; International; Lead; Memory; Mining; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pathogenesis; Patient Care; Phenotype; Population; Prevalence; Production; Public Domains; Reporting; Signal Transduction; Single Nucleotide Polymorphism; TCF7L2 gene; Techniques; Time; Translating; Transposase; Untranslated RNA; Variant; base; brain tissue; causal variant; chromosome conformation capture; cognitive ability; effective therapy; endoplasmic reticulum stress; genetic variant; genome editing; genome wide association study; genomic data; genomic locus; glycogen synthase kinase 3 beta; human old age (65+); human pluripotent stem cell; induced pluripotent stem cell; lifestyle factors; nerve stem cell; promoter; tau Proteins; tau-1; trait

ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impacts in excess of 5 million Americans over the age 65 years old. AD disrupts memory and cognitive abilities, and there are currently no effective therapies able to slow or halt its progression. Although environmental and lifestyle factors have been implicated in its pathogenesis, AD is considered a complex disorder with a clear genetic component. Intense genome wide association study (GWAS) efforts through large-scale collaborations have been successful in discovering genetic loci robustly associated with AD beyond the classic APOE locus. However, GWAS only reports genomic signals associated with a given trait and not necessarily the precise localization of culprit genes. As such, over the past ten years, GWAS has not strictly represented a decade of gene target discovery, rather it has simply been a decade of signal discovery. One clear example of this is highlighted by the recent progress in characterizing the FTO locus in obesity. The GWAS signal that resides within an intronic region of FTO has in fact been recently shown to primarily influence the expression of the IRX3 and IRX5 genes nearby rather than the `host' gene itself, suggesting that this variant is in an enhancer embedded in one gene but influencing the expression of others. So a key question remains: is this the case with AD association signals as well? Indeed, we have already addressed the most significant GWAS finding in type 2 diabetes reported to date, namely genetic variation within the transcription factor 7-like 2 (TCF7L2) gene, which the P.I. on this application first described in 2006. Through the use of chromatin conformation capture and CRISPR/Cas9 genome editing techniques, we have evidence that a culprit gene at this locus is ACSL5. Since we already have a dedicated infrastructure in place to conduct such `variant to gene mapping' efforts, including CHOP's established Human Pluripotent Stem Cell core, our team is poised to determine how GWAS- implicated AD loci affect the expression and function of specific genes during neurodegeneration within corresponding topologically associated domains (TADs). The application of `3D Genomics' and CRISPR based techniques in the relevant cellular models of iPSC-derived neural progenitor cells (NPCs) and terminally differentiated neurons is particularly timely, as it will aid in pinpointing causal gene(s) at established AD GWAS signals when combined with `Assay for Transposase Accessible Chromatin sequencing' (ATAC-seq) to ascertain a shortlist of putative causal SNPs, which will almost entirely be non-coding, and that coincide with open chromatin. Only by uncovering the causative genes related to GWAS-identified genetic variants, and understanding how they operate, can we truly translate these high value GWAS reports in to meaningful benefits for patient care.

摘要 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，影响超过500万人， 65岁以上的美国人。AD会破坏记忆和认知能力，目前还没有 有效的治疗能够减缓或停止其进展。尽管环境和生活方式因素一直是 由于AD的发病机制与遗传有关，因此AD被认为是一种具有明确遗传成分的复杂疾病。 通过大规模合作进行的密集的全基因组关联研究（GWAS）工作已经完成， 成功地发现了与经典APOE基因座之外的AD强相关的遗传基因座。然而，在这方面， GWAS仅报告与给定性状相关的基因组信号，而不一定是基因组信号的精确定位 罪魁祸首基因因此，在过去的十年中，GWAS并不严格代表基因靶向的十年 发现，而不是仅仅是十年的信号发现。 一个明显的例子是最近在表征肥胖症中FTO基因座方面的进展。的 位于FTO内含子区域内的GWAS信号事实上最近已被证明主要与FTO的内含子区域相关。 影响附近IRX 3和IRX 5基因的表达，而不是“宿主”基因本身，这表明， 这种变体存在于嵌入一个基因的增强子中，但影响其他基因的表达。所以一把钥匙 问题仍然存在：AD关联信号是否也是这种情况？ 事实上，我们已经讨论了迄今为止报道的2型糖尿病中最重要的GWAS发现， 即转录因子7样2（TCF 7 L2）基因内的遗传变异，P.I. on this 2006年首次提出申请。通过使用染色质构象捕获和CRISPR/Cas9 通过基因组编辑技术，我们有证据表明这个位点的罪魁祸首基因是ACSL 5。 由于我们已经有了专门的基础设施来进行这种“从变异到基因绘图”的努力， 包括CHOP建立的人类多能干细胞核心，我们的团队准备确定GWAS- 牵涉的AD基因座影响神经变性过程中特定基因的表达和功能， 对应的拓扑关联域（TADs）。基于“3D基因组学”和CRISPR的应用 iPSC衍生的神经祖细胞（NPC）的相关细胞模型中的技术， 分化的神经元是特别及时的，因为它将有助于在已建立的AD GWAS中精确定位致病基因。 当与“转座酶可重复染色质测序试验”（ATAC-seq）结合时， 确定一个假定的因果SNP的短名单，这将几乎完全是非编码的，并符合 开放染色质。 只有通过揭示与GWAS鉴定的遗传变异相关的致病基因，并了解如何 我们能否真正将这些高价值的GWAS报告转化为对患者护理有意义的益处。

项目成果

3D promoter architecture re-organization during iPSC-derived neuronal cell differentiation implicates target genes for neurodevelopmental disorders.

• DOI: 10.1016/j.pneurobio.2021.102000
• 发表时间: 2021-06
• 期刊: Progress in neurobiology
• 影响因子: 6.7
• 作者: Su C;Argenziano M;Lu S;Pippin JA;Pahl MC;Leonard ME;Cousminer DL;Johnson ME;Lasconi C;Wells AD;Chesi A;Grant SFA
• 通讯作者: Grant SFA