Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN− nuclei from the prenatal human frontal cortex, and tested enrichment of single-nucleotide polymorphism (SNP) heritability for five neuropsychiatric disorders (autism spectrum disorder, attention deficit hyperactivity disorder [ADHD], bipolar disorder, major depressive disorder, and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder, and schizophrenia within open chromatin regions (OCRs) mapped in bulk fetal frontal cortex, and for all five tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in OCRs identified in fetal frontal cortex NeuN− as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped OCRs for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN− cells of the prenatal brain.

中文翻译：

---

产前额叶皮层活性基因调控位点及其在神经精神疾病中的作用

常见的遗传变异似乎通过对基因调控的影响在很大程度上影响了神经精神疾病的风险。因此，可以通过测试在特定组织或细胞类型中运作的调控基因组区域内相关遗传变异的富集来阐明这些条件的生物学。在这里，我们使用高通量测序 (ATAC-Seq) 的转座酶可及染色质测定来绘制来自产前人类额叶皮层的大块组织、NeuN+ 和 NeuN- 核中的开放染色质（活性调节基因组区域的索引） ，并测试了五种神经精神疾病（自闭症谱系障碍、注意力缺陷多动障碍 [ADHD]、双相情感障碍、重度抑郁症、和精神分裂症）在这些地区。我们观察到多动症、重度抑郁症和精神分裂症的 SNP 遗传性显着富集，这些区域位于胎儿额叶皮质的开放染色质区域 (OCR) 中，并且对于所有五种测试的神经精神疾病，当我们将这些位点限制为指示增强剂的重叠组蛋白修饰时(H3K4me1) 或胎儿大脑中的启动子 (H3K4me3)。在胎儿额叶皮层 NeuN- 以及与胎儿大脑 H3K4me1 或 H3K4me3 位点重叠的 NeuN+ 核中鉴定的 OCR 中，神经精神疾病的 SNP 遗传性显着富集。我们还展示了我们绘制的 OCR 用于在神经精神疾病的全基因组显着风险位点优先考虑潜在功能性 SNP 的效用。