Kouakou Manuela R, Cameron Darren, Hannon Eilis, Dempster Emma L, Mill Jonathan, Hill Matthew J, Bray Nicholas J
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
University of Exeter Medical School, University of Exeter, Exeter, UK.
Am J Med Genet B Neuropsychiatr Genet. 2021 Sep;186(6):376-388. doi: 10.1002/ajmg.b.32877. Epub 2021 Oct 10.
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.
常见的基因变异似乎主要通过对基因调控的影响来极大地影响神经精神疾病的风险。因此，通过检测特定组织或细胞类型中起作用的调控基因组区域内相关基因变异的富集情况，有可能揭示这些疾病的生物学机制。在这里，我们使用了带有高通量测序的转座酶可及染色质分析（ATAC-Seq）来绘制产前人类额叶皮质的大块组织、NeuN+和NeuN-细胞核中的开放染色质（活性调控基因组区域的指标），并测试了这些区域内五种神经精神疾病（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）的单核苷酸多态性（SNP）遗传力的富集情况。我们观察到，在胎儿额叶皮质大块组织中绘制的开放染色质区域（OCRs）内，ADHD、重度抑郁症和精神分裂症的SNP遗传力有显著富集，当我们将这些位点限制在与胎儿脑中指示增强子（H3K4me1）或启动子（H3K4me3）的组蛋白修饰重叠的位点时，所有五种测试的神经精神疾病均如此。神经精神疾病的SNP遗传力在胎儿额叶皮质NeuN-以及与胎儿脑H3K4me1或H3K4me3位点重叠的NeuN+细胞核中鉴定出的OCRs中显著富集。我们还证明了我们绘制的OCRs在优先考虑神经精神疾病全基因组显著风险位点处潜在功能性SNP方面的效用。我们的数据为一系列神经精神疾病的早期神经发育成分提供了证据，并突出了产前脑NeuN+和NeuN-细胞中活跃的调控基因组区域的重要作用。
