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。

基本信息

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
项目类别：
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

项目摘要

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。具有巨大影响的罕见变异为描述复杂的因果机制提供了绝佳的机会最近，精神分裂症的大规模外显子组测序发现，罕见的蛋白质截短和包含 1A (SETD1A) 的 SET 结构域中的错义变体与大约 4 至 20 倍相关精神分裂症的风险增加，使其成为大约 10 个具有强 SETD1A 编码负责赖氨酸 4 上三甲基化的染色质修饰酶。组蛋白 3 尾 (H3K4me3)，活性启动子处的重要组蛋白修饰，表征活性启动子的作用。 SETD1A 变体已成为了解因果机制最令人兴奋的前景之一然而，研究这些影响却受到两个关键因素的阻碍。障碍：首先，由于 SETD1A 变体非常罕见，因此很难确定足够数量的其次，部分出于同样的原因，也出现了这种情况。没有关于人类神经细胞中自然发生的 SETD1A 变体的研究。在这里，我们建议进行实验。利用我们发现的七个有害的、非同义的 SETD1A 克服这两个障碍在当地可接触到的创始人群体（旧秩序阿米什人）中丰富的变体我们将总共招募 128 名。 SETD1A 变体的阿米什携带者及其血亲确定深层认知和精神症状表型，以及有关等位基因异质性、等位基因频率依赖性、剂量的测试假设接下来，我们将获得诱导多能性。来自这些个体的一个子集的干细胞来识别细胞和神经发育表型，在细胞水平上表征等位基因异质性，并检验细胞表型可以被最后，我们将检验 SETD1A 变体改变 H3K4me3 水平的假设。使用尖端的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、认知缺陷、细胞增殖减少、增加易受 DNA 损伤、神经玫瑰花结形成效率低下、神经突生长缺陷以及神经干细胞过早细胞周期退出和过早成熟的转录特征。