GABRA2 genetic variants and chromosome conformation in induced pluripotent stem cell-derived neural cells

诱导多能干细胞衍生神经细胞中的 GABRA2 遗传变异和染色体构象

基本信息

批准号：
9976412
负责人：
Alexandra Marie Goetjen
金额：
$ 5.05万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976412
关键词：
Adult Affect Alleles American Anchored Polymerase Chain Reaction Antibodies Binding Sites Biological Brain CRISPR/Cas technology Chromatin Chromatin Loop Chromosomes Chronic Code Computer software DNA Binding DNA Microarray Chip Data Development Disease Distal Early Diagnosis Elements Emotional Environmental Risk Factor European Exons Family Functional disorder Gene Cluster Gene Expression Genes Genetic Genetic Enhancer Element Genetic Risk Genetic Transcription Goals Haplotypes Heritability High Prevalence Homozygote Individual Introns Lead Libraries Link Linkage Disequilibrium Mediating Methods Methylation Molecular Conformation Neurons Oligonucleotides Patients Phenotype Polymerase Chain Reaction Population Prevention program Preventive Intervention Production Proteins Published Comment Reporting Risk Sampling Single Nucleotide Polymorphism Site Societies Substance Use Disorder Testing Trans-Activators Transcriptional Regulation United States Untranslated RNA Variant alcohol effect alcohol use disorder base chromatin immunoprecipitation chromatin protein chromosome conformation capture differential expression epigenome gamma-Aminobutyric Acid genetic variant genome editing genomic locus improved individualized medicine individualized prevention induced pluripotent stem cell intervention program markov model nerve stem cell neural circuit neuropsychiatric disorder patient population promoter psychologic relating to nervous system virtual

项目摘要

Project Summary Alcohol use disorders (AUDs) affect approximately 8.5% of the United States population. Risk of developing an AUD is influenced by both genetic and environmental factors, with heritability estimated to be between 50 and 60%. While several genetic variants have been associated with increased risk of developing an AUD, little is known about the biological mechanisms linking such variants to the pathophysiology of AUD. One of the most commonly-examined single-nucleotide polymorphisms (SNPs) associated with increased genetic risk of developing an AUD is rs279858, a synonymous SNP located in exon 5 of GABRA2. This tag-SNP serves as a bookmark for a 140 kilobase (kb) haplotype block containing a number of SNPs that are in high linkage disequilibrium (LD) and are associated with increased genetic risk for developing an AUD. The absence of a linked coding variant suggests that AUD-associated risk in this region due to an unidentified functional non- coding variant that influences developmentally-regulated gene expression of GABRA2 or nearby genes. Using induced pluripotent stem cell (iPSC)-derived neurons, it has been reported that decreased expression of GABRA2 on chromosome 4p12 as well as that of the GABRA4 and GABRB1 subunit genes 500kb distal to GABRA2 is correlated with the rs279858 risk C-allele, as compared to iPSC-derived neurons that are homozygous for the non-risk-associated allele. Furthermore, promoter methylation analysis suggests that in CC lines, long-range intrachromosomal interactions may bring enhancer elements into close physical proximity to GABRA2 and subsequently alter the transcription of the chr4p12 GABA gene cluster, as compared to a more-localized mechanism of transcriptional control in TT homozygotes. The goal of this project is to define the elements of the long-range interactions that appear to influence transcription from this region, to better understand the proximal genetic effects of this AUD-associated variation and thereby stimulate further understanding of how it may relate to risk of developing AUD.

项目摘要酒精使用障碍（AUD）影响了大约8.5％的美国人口。发展风险 AUD受遗传因素和环境因素的影响，遗传力估计在50之间和60％。虽然几种遗传变异与发展AUD的风险增加有关，但很少关于将这种变异与AUD的病理生理学联系起来的生物学机制已知。中的一个与增加的遗传风险相关的最常见的单核苷酸多态性（SNP）开发AUD的是RS279858，这是位于Gabra2外显子5中的同义SNP。这个标签-SNP用作 140千射线群（KB）单倍型块的书签，该型块包含许多以高链接为单位的SNP 不平衡（LD），与发展AUD的遗传风险增加有关。没有链接的编码变体表明，由于身份不明的功能性非 - 编码变体影响GABRA2或附近基因的发育调节基因表达。使用诱导多能干细胞（IPSC）衍生的神经元，据报道 GABRA2在4p12染色体上以及GABRA4和GABRB1亚基基因500KB远端与IPSC衍生的神经元相比非风险相关等位基因的纯合子。此外，启动子甲基化分析表明 CC线，远程内肉体内相互作用可能会使增强子元素陷入密切的物理接近度与Gabra2相比 TT纯合子中转录控制的更加定位的机制。该项目的目的是定义似乎影响从该区域转录的远程相互作用的要素了解这种AUD相关变异的近端遗传效应，从而进一步刺激了解它如何与发展AUD的风险有关。