Effects of allele-specific open chromatin Genetic variants in noncoding regions of the genome may underlie the development of disease. However, we are just beginning to tease apart the function of such variants associated with neuropsychiatric disease. Using five types of neural progenitor cells derived from 20 human induced pluripotent stem cell lines, Zhang et al. looked at allele-specific open chromatin (ASoC) variants. Many ASoC variants overlapped with genomic elements, such as transcription factor binding sites, and loci identified in genome-wide association studies for neurological traits. From the experimental and computational analyses, they identified single-nucleotide polymorphisms and illuminate how one schizophrenia-associated variant affects neurodevelopment. Science, this issue p. 561 Analysis of allele-specific open chromatin provides a functional mechanism underlying noncoding neuropsychiatric risk variants. Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)–derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.

中文翻译：

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人类 iPSC 神经元中等位基因特异性开放染色质阐明功能性疾病变异


等位基因特异性开放染色质的影响基因组非编码区域的遗传变异可能是疾病发生的基础。然而，我们才刚刚开始梳理这些与神经精神疾病相关的变异的功能。张等人使用源自 20 种人类诱导多能干细胞系的五种神经祖细胞。研究了等位基因特异性开放染色质 (ASoC) 变体。许多 ASoC 变体与基因组元件重叠，例如转录因子结合位点，以及神经性状全基因组关联研究中确定的基因座。通过实验和计算分析，他们确定了单核苷酸多态性，并阐明了一种与精神分裂症相关的变异如何影响神经发育。科学，本期第 14 页。 561 对等位基因特异性开放染色质的分析提供了非编码神经精神风险变异的功能机制。大多数神经精神疾病风险变异位于非编码序列中，缺乏功能解释。由于调控序列通常位于开放染色质中，因此我们推断神经精神疾病风险变异可能会影响神经发育过程中染色质的可及性。使用人类诱导多能干细胞 (iPSC) 衍生的神经元来模拟发育中的大脑，我们识别出了数千种表现出等位基因特异性开放染色质 (ASoC) 的遗传变异。这些神经元 ASoC 部分是由转录因子结合改变驱动的，在大脑基因增强子和表达数量性状位点中过多，并且经常通过染色质接触与远端基因相关。 ASoC 富含与脑部疾病相关的遗传变异，从而能够识别功能性精神分裂症风险变异及其顺式靶基因。这项研究强调 ASoC 作为非编码神经精神风险变异的功能机制，为识别疾病致病变异和基因提供了强大的框架。