Multi-scale consequences of variants in the schizophrenia risk gene SETD1A in a population isolate.

群体分离中精神分裂症风险基因 SETD1A 变异的多尺度后果。

• 批准号: 10678897
• 负责人: Seth Abrams Ament
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678897
• 关键词: Affect; Alleles; Amish; Behavioral; Blood; Brain; Brain Diseases; Cell Cycle; Cell Proliferation; Cells; ChIP-seq; Characteristics; Chromatin; Cognition; Cognitive; Cognitive deficits; Complex; DNA Damage; Data; Dependence; Development; Disease; Dose; Enzymes; Founder Generation; Gene Expression Profile; Gene Expression Regulation; Gene Frequency; Genes; Genetic Transcription; Heterogeneity; Heterozygote; Histones; Human; Individual; Lysine; Mediating; Methylation; Modeling; Molecular; Multiomic Data; Neurites; Neurobehavioral Manifestations; Neurobiology; Neurons; Phenotype; Pluripotent Stem Cells; Population; Protein Truncation; Public Health; RNA; Regulator Genes; Resources; Risk; SET Domain; Schizophrenia; Severities; Tail; Techniques; Technology; Testing; Time; United States; Variant; Work; XCL1 gene; brain cell; chromatin modification; clinical heterogeneity; clinical phenotype; cohort; developmental disease; epigenetic therapy; exome sequencing; experimental study; genome editing; high risk; histone modification; human embryonic stem cell line; in vivo; induced pluripotent stem cell; insight; multiple omics; nerve stem cell; network models; neural; neurodevelopment; novel therapeutics; pharmacologic; premature; promoter; psychiatric symptom; psychosis risk; public health relevance; rare variant; recruit; response; risk variant; schizophrenia risk

Project Summary. Rare variants with large effects provide excellent opportunities to characterize causal mechanisms for complex disorders. Recently, large-scale exome sequencing of schizophrenia found that rare protein-truncating and missense variants in SET Domain Containing 1A (SETD1A) are associated with approximately 4- to 20-fold increased risk for schizophrenia, making this the top risk gene (P = 2.0e-12) among about ten genes with strong support. SETD1A encodes a chromatin modifying enzyme responsible for tri-methylation of lysine 4 on the histone 3 tail (H3K4me3), an important histone modification at active promoters. Characterizing the effects of SETD1A variants has emerged as one of the most exciting prospects to understand causal mechanisms underlying risk for schizophrenia. However, interrogating these effects has been hindered by two critical obstacles: First, since SETD1A variants are very rare, it has been difficult to ascertain sufficient numbers of carriers to fully characterize SETD1A’s clinical phenotype. Second, in part for the same reason, there have been no studies of naturally occurring SETD1A variants in human neural cells. Here, we propose experiments to overcome both of these obstacles, leveraging our discovery of seven deleterious, nonsynonymous SETD1A variants enriched in a locally accessible founder population, the Old Order Amish. We will recruit a total of 128 Amish carriers of SETD1A variants and their blood relatives, ascertain deep cognitive and psychiatric symptom phenotypes, and test hypotheses regarding allelic heterogeneity, allele frequency dependence, dose dependence, and interactions with polygenic risk from common variants. Next, we will obtain induced pluripotent stem cells from a subset of these individuals to identify cellular and neurodevelopmental phenotypes, characterize allelic heterogeneity at a cellular level, and test the hypothesis that cellular phenotypes can be rescued by restoring levels of H3K4me3. Finally, we will test the hypothesis that SETD1A variants alter the chromatin potential of developing neurons, using cutting-edge single-cell multi-omic technologies and network modeling techniques. Our exciting preliminary results demonstrate that Amish-enriched SETD1A variants are associated with increased risk for psychosis, cognitive deficits, reduced cellular proliferation, increased vulnerability to DNA damage, inefficient formation of neural rosettes, deficits in neurite outgrowth, and transcriptional signatures of premature cell cycle exit and premature maturation in neural stem cells.

项目摘要。 具有大效应的罕见变异为描述复杂疾病的原因机制提供了极好的机会 精神错乱。最近，对精神分裂症的大规模外显子组测序发现，罕见的蛋白质截断和 包含1A的SET结构域(SETD1A)中的错义变体与大约4-20倍相关 增加患精神分裂症的风险，使其成为约10个基因中最危险的基因(P=2.0e-12) 支持。SETD1A编码一种染色质修饰酶，负责赖氨酸4的三甲基化 组蛋白3尾部(H3K4me3)，一个重要的组蛋白修饰的活性启动子。描述以下因素的影响 SETD1A变异体已经成为理解因果机制的最令人兴奋的前景之一 精神分裂症的潜在风险。然而，审问这些影响受到了两个关键因素的阻碍 障碍：首先，由于SETD1A变异体非常罕见，很难确定足够数量的 携带者可以完全确定SETD1A的临床表型。其次，在一定程度上，出于同样的原因， 没有关于人类神经细胞中自然产生的SETD1A变体的研究。在这里，我们建议进行实验，以 克服这两个障碍，利用我们发现的七个有害的、非同义的SETD1A 变种丰富了当地可访问的创始人群体，旧秩序阿米什人。我们将总共招聘128人 SETD1A变异体的阿米什携带者及其血缘亲属，确定深层认知和精神症状 表型，以及关于等位基因异质性、等位基因频率依赖性、剂量 依赖，以及与常见变种的多基因风险的相互作用。接下来，我们将获得诱导多能性 从这些个体的子集中提取干细胞来鉴定细胞和神经发育表型， 在细胞水平上表征等位基因的异质性，并测试细胞表型可以是 通过恢复H3K4me3的水平而获救。最后，我们将测试SETD1A变异会改变 利用尖端单细胞多组学技术和网络研究发育中神经元的染色质潜力 建模技术。我们令人兴奋的初步结果表明，富含阿米什的SETD1A变体是 与精神病风险增加、认知障碍、细胞增殖减少、 易受DNA损伤，神经花环形成效率低下，神经突起生长缺陷，以及 神经干细胞中早熟细胞周期退出和早熟的转录特征。